CN101115748B - Acetamide compounds as fungicides - Google Patents

Acetamide compounds as fungicides Download PDF

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Publication number
CN101115748B
CN101115748B CN2005800400770A CN200580040077A CN101115748B CN 101115748 B CN101115748 B CN 101115748B CN 2005800400770 A CN2005800400770 A CN 2005800400770A CN 200580040077 A CN200580040077 A CN 200580040077A CN 101115748 B CN101115748 B CN 101115748B
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compound
base
formula
methyl
alkyl
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CN101115748A (en
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R·萨蒙
D·P·培根
E·J·T·克里斯托尔
D·W·兰顿
A·J·尼
G·R·芒斯
L·夸兰塔
H-G·布伦纳
R·博德涅斯
F·塞德鲍姆
F·墨菲凯萨比
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Syngenta Participations AG
Syngenta Ltd
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Syngenta Participations AG
Zeneca Ltd
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    • A01N39/00—Biocides, pest repellants or attractants, or plant growth regulators containing aryloxy- or arylthio-aliphatic or cycloaliphatic compounds, containing the group or, e.g. phenoxyethylamine, phenylthio-acetonitrile, phenoxyacetone
    • A01N39/02—Aryloxy-carboxylic acids; Derivatives thereof
    • A01N39/04—Aryloxy-acetic acids; Derivatives thereof
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Compounds of the general formula (I); wherein the substituents are as defined in claim 1, are useful as fungicides.

Description

Acetamide compounds as fungicides
The present invention relates to that new N-replaces-2-alkylthio-2-(aryloxy of replacement and heteroaryloxy) alkylamide and sulfinyl and sulfonyl-derivatives.Also relate to its preparation method, contain the composition of described material and use described material, particularly the method for the fungi infestation of plant antimycotic.
Some pyridyloxy (sulfenyl) alkanoic acid amides and heteroaryloxy (sulfenyl) alkanoic acid amides derivative and be disclosed in WO 99/33810 and JP2001-89453 as the agricultural and the purposes of gardening bactericide.The phenoxy group butyramide of some replacement and be disclosed in EP0,001,721 as the purposes of fungicides.Some phenoxy group and pyridyloxy alkanoic acid amides and be disclosed in WO 04/047537, WO 04/048316, WO 04/048315 and WO03/048128 as the purposes of mycocide.Some phenoxy group and heteroaryloxy alkoxyl group acetamide derivative and be disclosed in WO 04/052100, WO 04/048337 and WO 04/047538 as the purposes of mycocide.The 2-alkyl sulphonyl of some replacement-2-phenoxyalkyl N-anilide is disclosed in JP61 as the purposes of sensitive photographic material, and 86702 and US4,286,053.
The present invention relates to provide main special N-as plant fungicide replaces-2-alkylthio-2-(aryloxy of replacement and heteroaryloxy) alkylamide and sulfinyl and sulfonyl-derivatives.
Therefore, the invention provides the compound of general formula (1):
Figure G05840077020070525D000011
Wherein
Ar is aryl (for example phenyl, naphthyl), and (5-unit heteroaryl is pyrryl for example, furyl, thienyl, pyrazolyl, imidazolyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, triazolyl ， oxadiazole base, thiadiazolyl group, tetrazyl for heteroaryl; 6-unit heteroaryl is pyridyl for example, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl; With benzene condensed 5-unit heteroaryl, indyl for example, benzofuryl, benzothienyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base, indazolyl, Ben Bing oxadiazole base, diazosulfide base, benzotriazole base; With two phenyl ring condensed 5-unit heteroaryls, dibenzofuran group for example, dibenzothiophene base; With a phenyl ring and pyridine ring condensed 5-unit heteroaryl for example cumarone and pyridyl, thionaphthene and pyridyl; With benzene condensed 6-unit heteroaryl, quinolyl for example, isoquinolyl, or optional one or two heteroatomic fractional saturation that is independently selected from N, O or S or complete saturated cyclic group (the 9H-fluorenyl for example that contains quinazolyl, quinoxalinyl),, 1,2,3, the 4-tetralyl, indanyl, 1,3-benzodioxole base, 1,3-benzo oxa-thia cyclopentenyl, 1,3-benzo dithia cyclopentenyl)
Described aryl, heteroaryl or part or complete saturated cyclic group are optional to be replaced by one, two, three, four or five substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl (C 1-6) alkyl (for example phenmethyl), aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) u(C 1-6) alkyl, wherein u is 0,1 or 2 and alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyl) ,-OSO by halogen 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyloxy) ,-CONR by halogen uR v,-COR u,-CO 2R u,-CR u=NR v,-NR uR v,-NR uCOR v,-NR uCO 2R v,-SO 2NR uR vOr-NR uSO 2R w, R wherein wBe the optional C that is replaced by halogen 1-6Alkyl, R uAnd R vBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), perhaps ,-CONR uR vOr-SO 2NR uR vSituation under, can be in conjunction with forming 5-or 6-unit ring, described 5-or 6-unit ring contain a nitrogen-atoms, sulphur atom, saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part are optional to be substituted;
R 1Be C 1-4Alkyl (for example methyl, ethyl), halo (C 1-4) alkyl (CF for example 3, CF 2H, CF 2Cl, CH 2CH 2F) or C 3-4Cycloalkyl;
R 2Be H, C 1-8Alkyl (for example methyl, ethyl, sec.-propyl), C 3-4Cycloalkyl (for example cyclopropyl), C 2-8Thiazolinyl (for example allyl group, 3-methyl-but-2-ene base, 4-methyl-penta-2-thiazolinyl), cyano group (C 1-4) alkyl (for example cyano methyl, cyano ethyl), C 1-4Alkoxyl group (C 1-4) alkyl (for example methoxymethyl, ethoxyethyl group), C 1-4Alkoxyl group (C 1-4) alkoxyl group (C 1-4) alkyl (for example methoxy ethoxy methyl) or benzyloxy (C 1-4) alkyl (for example benzyloxy methyl), wherein the phenyl ring of phenmethyl part is optional by C 1-4Alkoxyl group replaces;
R 3Be-(CR aR b) p(CR cR d) q(X) r(CR eR f) sR 4, wherein
R a, R b, R c, R d, R eAnd R fBe H independently, C 1-4Alkyl (for example methyl), halogen (for example chlorine), cyano group, hydroxyl, C 1-4Alkoxyl group (for example methoxyl group) or C 1-4Alkoxy carbonyl (for example ethoxy carbonyl), or R aR b, R cR dOr R eR fCan be in conjunction with forming 3-8 unit ring, described ring is chosen wantonly and is contained aerobic, sulphur or nitrogen-atoms,
X is (CO), (CO) O, O (CO), O, S (O) t, wherein t is 0,1 or 2, NH or N (C 1- 6) alkyl,
P, r and s are 0 or 1,
Q is 0,1 or 2,
R 4Be C 1-6Alkyl (for example methyl, ethyl, sec.-propyl, normal-butyl, the tertiary butyl), described alkyl optional by one, two or three are independently selected from following substituting group and replace: halogen (for example fluorine, chlorine), cyano group or hydroxyl, C 1-4Alkoxyl group (C 1-4) alkyl (for example methoxymethyl, ethoxyethyl group), C 1-4Alkoxyl group-(C 1-4) alkoxyl group (C 1-4) alkyl (for example methoxy ethoxy methyl), benzyloxy (C 1-4) alkyl (for example benzyloxy methyl), C 2-6Alkene oxygen base (for example allyloxy) ,-S (O) x(C 1-6) alkyl, wherein x is 0,1 or 2 and alkyl is optional is replaced by halogen (fluorine particularly, for example 2,2,2-trifluoro ethylmercapto group), single-or two-(C 1-6) alkylamino (for example N-methylamino, N, N-dimethylamino) or three (C 1-4) alkyl silyl (for example trimethyl silyl), or
R 4Be C 2-6Thiazolinyl (for example vinyl, allyl group), described thiazolinyl optional by one, two or three are independently selected from following substituting group and replace: halogen (for example chlorine), cyano group, hydroxyl, C 1-6Alkoxyl group (for example methoxyl group), C 1-6Alkyl-carbonyl (for example ethanoyl), C 1-6Alkoxy carbonyl (for example methoxycarbonyl) or optional by C 1-4The phenyl that alkoxyl group replaces, or
R 4Be-CH 2-C ≡ C-R 5, wherein
R 5Be H, C 1-8Alkyl, C 3-6Cycloalkyl or C 3-6Cycloalkyl (C 1-4) alkyl, alkyl or cycloalkyl wherein is optional by halogen, hydroxyl, C 1-6Alkoxyl group, C 1-3Alkoxyl group (C 1-3) alkoxyl group, cyano group, C 1-4Alkyl carbonyl oxy, amino carbonyl oxygen base or list-or two (C 1-4) alkyl amino carbonyl oxy, three (C 1-4) alkyl siloxy ,-S (O) g(C 1-6) alkyl (wherein g is 0,1 or 2) replacement, or
R 5Be optional substituted aryl (for example phenyl), optional substituted aryl (C 1-4) alkyl (for example phenmethyl), optional substituted aryloxy (C 1-4) alkyl (for example phenoxymethyl), optional substituted aryl (C 1-4) alkoxyl group (C 1-4) alkyl (for example benzyloxy methyl), optional substituted heteroaryl (for example pyridyl, thienyl, pyrazolyl, imidazolyl, triazolyl) or optional substituted heteroaryl (C 1-4) alkyl (for example pyridylmethyl, phthalimido ethyl), optional substituted heteroaryloxy (C 1-4) alkyl (for example thiophene oxy methyl) or optional substituted heteroaryl-(C 1-4) alkoxyl group (C 1-4) alkyl (for example thienyl methoxymethyl),
R wherein 5Optional substituted aryl and heteroaryl ring described in the definition or part are optional to be replaced by one, two or three substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl (C 1-6) alkyl (for example phenmethyl), aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) g(C 1-4) alkyl, wherein g is 0,1 or 2 and alkyl is optional is replaced by halogen (fluorine particularly, trifluoromethyl sulfonyl for example ,-OSO 2(C 1-4) alkyl, alkyl wherein is optional to be replaced (particularly fluorine, for example trifluoromethyl sulfonyloxy) ,-CONR by halogen gR h,-COR g,-CO 2R g,-CR g=NR h,-NR gR h,-NR gCOR h,-NR gCO 2R h,-SO 2NR gR hOr-NR gSO 2R i, R wherein iBe the optional C that is replaced by halogen 1-6Alkyl, R gAnd R hBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), perhaps ,-CONR gR hOr-SO 2NR gR hSituation under, can be in conjunction with forming 5-or 6-unit ring, described 5-or 6-unit ring contain a nitrogen-atoms, sulphur atom, saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part are optional to be substituted, or
R 4Be C 3-6Cycloalkyl (for example cyclopropyl, cyclopentyl, cyclohexyl), C 5-6Cycloalkenyl group (for example cyclopentenyl, cyclohexenyl), aryl (for example phenyl, naphthyl), (5 yuan of heteroaryls are pyrryl for example, furyl for heteroaryl, thienyl, pyrazolyl, imidazolyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, triazolyl ， oxadiazole base, thiadiazolyl group, tetrazyl; 6-unit heteroaryl, pyridyl for example, pyridazinyl, pyrimidyl, or optional one or two heteroatomic fractional saturation that is independently selected from N, O or S or complete saturated cyclic group (pyrrolidyl for example, the tetrahydrofuran base of containing pyrazinyl, triazinyl),, tetrahydro-thienyl, piperidyl, dioxolanyl, morpholinyl, thiadiazine base, 1,2,3, the 4-tetralyl, 2, the 3-dihydro benzo furyl)
Described aryl, heteroaryl or part or complete saturated cyclic group are optional to be replaced by one, two or three substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl, n-pentyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example difluoro-methoxy, trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group ,-SF 5,-S (O) x(C 1-6) alkyl, wherein x is 0,1 or 2 and alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyl) ,-OSO by halogen 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyloxy) ,-CONR by halogen xR y,-CON (OR x) R y,-COR x,-CO 2R x,-CR x=NR y,-NR xR y,-NR xCOR y,-NR xCO 2R y,-SO 2NR xR yOr-NR xSO 2R z, R wherein zBe the optional C that is replaced by halogen 1-8Alkyl, R xAnd R yBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), or
R 2And R 3Can be in conjunction with forming saturated or undersaturated 5-or 6-unit ring, described ring is optional to contain O or S atom (Pyrrolidine base for example, thiazolidyl, piperidyl, morpholinyl, thio-morpholinyl, 2,5-pyrrolin base) and optional by one, two or three halogens (for example chlorine), C 1-4Alkyl (for example methyl, ethyl) or single-or two-(C 1-4) alkyl amino-carbonyl replaces, or optionally contain nitrogen-atoms (for example piperazinyl), optional by C on nitrogen-atoms 1-4Alkyl replaces and described C 1-4Alkyl is optional by halogen, C 1-6Alkoxyl group or cyano group replace, and are perhaps describedly replaced by phenyl, and described phenyl is optional by nitro, C 1-4Alkyl, halo (C 1-4) alkyl (for example trifluoromethyl), C 1-4Alkyl-carbonyl (for example ethanoyl) or heteroaryl (for example pyridyl) replace, or
R 2And R 3Can be in conjunction with forming 6,6-unit saturated bicyclic (for example Decahydroisoquinolinpreparation); Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part can be chosen wantonly and be substituted;
L is O or S; With
N is 0,1 or 2.
Compound of the present invention contains at least one unsymmetrical carbon and may exist or exist as its mixture as enantiomer (or diastereomer to).In addition, when n is 1, compound of the present invention is a sulfoxide, and it can two kinds of optical siomerism forms exist, and adjacent carbon atom also can two kinds of optical siomerism forms exist.Therefore, general formula (1) compound can be used as racemoid, diastereomer or single enantiomer and exists, and the present invention includes the isomer mixture of all possible isomer or any ratio.For any given compound, can expect that a kind of ratios of the isomers another kind more has Fungicidally active.
Except as otherwise noted, suitable 1-6 carbon atom, a particularly 1-4 carbon atom that contains direct-connected or side chain form such as the moieties of alkyl and alkoxyl group, alkylthio etc.Example is a methyl, and ethyl is just with sec.-propyl and normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.When moieties contains 5 or 6 carbon atoms, example is n-pentyl and n-hexyl.The optional substituent suitable example of alkyl and part comprises halogen, hydroxyl, C 1-4Alkoxyl group and C 1-4Alkoxyl group (C 1-4) alkoxyl group, optional substituted aryl and optional substituted heteroaryl.When optional substituting group was halogen, haloalkyl or part be trichloromethyl or trifluoromethyl normally.
Except as otherwise noted, also suitable 2-6 of containing direct-connected or side chain form, particularly 2-4 carbon atom of thiazolinyl and alkynyl part.Example is allyl group, ethynyl and propargyl.Optional substituting group comprises halogen.
Halogen comprises fluorine, chlorine, bromine and iodine.The most normally fluorine, chlorine or bromine, normally fluorine or chlorine.
Aryl is phenyl normally, but also comprises naphthyl, anthryl and phenanthryl.
Heteroaryl normally contains one or more O, N or the heteroatomic 5-of S or 6-unit aromatic ring, can condense with one or more other aromatic rings or hetero-aromatic ring such as phenyl ring.Example is a thienyl, furyl, pyrryl ， isoxazolyl ， oxazolyl, thiazolyl ， oxadiazole base, pyrazolyl, imidazolyl, triazolyl, isothiazolyl, tetrazyl, thiadiazolyl group, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, benzofuryl, benzothienyl, dibenzofuran group, dibenzothiophene base, benzothiazolyl, benzoxazolyl, benzimidazolyl-, indyl, quinolyl, isoquinolyl, quinazolyl and quinoxalinyl and N-oxide compound and salt thereof suitably the time.Any aryl or heteroaryl are optional to be substituted.Except as otherwise noted, the substituting group that may exist comprises one or more following: halogen, hydroxyl, sulfydryl, C 1-6Alkyl (particularly methyl and ethyl), C 2-6Thiazolinyl (particularly allyl group), C 2-6Alkynyl (particularly propargyl), C 1-6Alkoxyl group (particularly methoxyl group), C 2-6Alkene oxygen base (particularly allyloxy), C 2-6Alkynyloxy group (particularly alkynes propoxy-), halo (C 1-6) alkyl (particularly trifluoromethyl), halo (C 1-6) alkoxyl group (particularly trifluoromethoxy) ,-S (O) m(C 1-6) alkyl, wherein m is 0,1 or 2 and alkyl is optional is replaced hydroxyl (C by halogen 1-6) alkyl, C 1-4Alkoxyl group (C 1-4) alkyl, C 1-4Alkoxyl group (C 1-4) alkoxyl group, C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, optional substituted aryl (particularly optional substituted phenyl), optional substituted heteroaryl (particularly optional substituted pyridyl or pyrimidyl), optional substituted aryloxy (particularly optional substituted phenoxy group), optional substituted heteroaryloxy (particularly optional substituted pyridyloxy or 2-pyrimidinyl oxy) is chosen substituted-S (O) wantonly mAryl, wherein m is 0,1 or 2 (particularly optional substituted thiophenyls), chooses substituted-S (O) wantonly mHeteroaryl, wherein m is 0,1 or 2 (particularly optional substituted pyridine sulfenyl or pyrimidine sulfenyls), optional substituted aryl (C 1-4) alkyl (particularly optional substituted phenmethyl, optional substituted styroyl and optional substituted phenyl n-propyl), wherein moieties is optional is replaced optional substituted heteroaryl (C by hydroxyl 1-4) alkyl (particularly optional substituted pyridyl-or pyrimidyl (C 1-4) alkyl), optional substituted aryl (C 2-4) thiazolinyl (particularly optional substituted phenyl vinyl), optional substituted heteroaryl (C 2-4) thiazolinyl (particularly optional substituted pyridyl vinyl or pyrimidyl vinyl), optional substituted aryl (C 1-4) alkoxyl group (particularly optional substituted benzyloxy and benzene oxyethyl group), optional substituted heteroaryl (C 1-4) alkoxyl group (particularly optional substituted pyridyl (C 1-4) alkoxyl group or pyrimidyl (C 1-4) alkoxyl group), optional substituted aryloxy (C 1-4) alkyl (particularly phenoxymethyl), optional substituted heteroaryloxy-(C 1-4) alkyl (particularly optional substituted pyridyloxy or 2-pyrimidinyl oxy (C 1-4) alkyl), choose substituted-S (O) wantonly m(C 1-4) alkylaryl, wherein m is 0,1 or 2 (particularly optional substituted benzylthio and benzene ethylmercapto groups), chooses substituted-S (O) wantonly m(C 1-4) miscellaneous alkyl aryl, wherein m is 0,1 or 2 (particularly optional substituted pyridyl (C 1-4) alkylthio or pyrimidyl (C 1-4) alkylthio), choose substituted-(C wantonly 1-4) alkyl S (O) mAryl, wherein m is 0,1 or 2 (particularly phenyl thiomethyls), chooses substituted-(C wantonly 1-4) alkyl S (O) mHeteroaryl, wherein m is 0,1 or 2 (particularly optional substituted pyridine sulfenyl (C 1-4) alkyl or pyrimidine sulfenyl (C 1-4) alkyl), acyloxy comprises C 1-4Alkanoyloxy (particularly acetoxyl group) and benzoyloxy, cyano group, isocyano-, thiocyano, isocyanide sulfenyl, nitro, NR gR h,-NHCOR g,-NHCONR gR h,-CONR gR h,-CO 2R g,-SO 2R i,-OSO 2R i,-COR g,-CR g=NR hOr-N=CR gR h, R wherein iBe C 1-4Alkyl, halo (C 1-4) alkyl, C 1-4Alkoxyl group, halo (C 1-4) alkoxyl group, C 1-4Alkylthio, C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, phenyl or benzyl, phenyl and phenmethyl are optional by halogen, C 1-4Alkyl or C 1-4Alkoxyl group replaces, R gAnd R hBe hydrogen independently, C 1-4Alkyl, halo (C 1-4) alkyl, C 1-4Alkoxyl group, halo (C 1-4) alkoxyl group, C 1-4Alkylthio, C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, phenyl or benzyl, phenyl and phenmethyl are optional by halogen, C 1-4Alkyl or C 1-4Alkoxyl group replaces.
Compound (1) particularly importantly, wherein Ar is aryl (for example phenyl, naphthyl), heteroaryl (5-unit heteroaryl, pyrryl for example, furyl, thienyl, pyrazolyl, imidazolyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, triazolyl ， oxadiazole base, thiadiazolyl group, tetrazyl; 6-unit heteroaryl, pyridyl for example, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl; With benzene condensed 5-unit heteroaryl, indyl for example, benzofuryl, benzothienyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base, indazolyl, Ben Bing oxadiazole base, diazosulfide base, benzotriazole base; With two phenyl ring condensed 5-unit heteroaryls, dibenzofuran group for example, dibenzothiophene base; With a phenyl ring and certain pyridine ring condensed 5-unit heteroaryl, for example cumarone and pyridyl, thionaphthene and pyridyl; With benzene condensed 6-unit heteroaryl, quinolyl for example, isoquinolyl, quinazolyl, quinoxalinyl), or part or complete saturated cyclic group, optional one or two heteroatoms that is independently selected from N, O or S (9H-fluorenyl for example that contains, 1,2,3, the 4-tetralyl, indanyl, 1,3-benzodioxole base, 1,3-benzo oxa-thia cyclopentenyl, 1,3-benzo dithia cyclopentenyl)
Described aryl, heteroaryl or part or complete saturated cyclic group are optional to be replaced by one, two, three, four or five substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl (C 1-6) alkyl (for example phenmethyl), aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) u(C 1-6) alkyl, wherein u is 0,1 or 2 and alkyl is optional is replaced by halogen (particularly fluorine, Lee is trifluoromethyl sulfonyl for example) ,-OSO 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyloxy) ,-CONR by halogen uR v,-COR u,-CO 2R u,-CR u=NR v,-NR uR v,-NR uCOR v,-NR uCO 2R v,-SO 2NR uR vOr-NR uSO 2R w, R wherein wBe the optional C that is replaced by halogen 1-6Alkyl, R uAnd R vBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), perhaps ,-CONR uR vOr-SO 2NR uR vSituation under, can be in conjunction with forming 5-or 6-unit ring, described ring contains a nitrogen-atoms, a sulphur atom, a saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part are optional to be substituted;
R 1Be C 1-4Alkyl (for example methyl, ethyl), halo (C 1-4) alkyl (CF for example 3, CF 2H, CF 2Cl, CH 2CH 2F) or C 3-4Cycloalkyl;
R 2Be H, C 1-8Alkyl (for example methyl, ethyl, sec.-propyl), C 3-4Cycloalkyl (for example cyclopropyl), C 2-8Thiazolinyl (for example allyl group, 3-methyl-but-2-ene base, 4-methyl-penta-2-thiazolinyl), cyano group (C 1-4) alkyl (for example cyano methyl, cyano ethyl), C 1-4Alkoxyl group (C 1-4) alkyl (for example methoxymethyl, ethoxyethyl group), C 1-4Alkoxyl group (C 1-4) alkoxyl group (C 1-4) alkyl (for example methoxy ethoxy methyl) or benzyloxy (C 1-4) alkyl (for example benzyloxy methyl), wherein the phenyl ring of phenmethyl part is optional by C 1-4Alkoxyl group replaces;
R 3Be-(CR aR b) p(CR cR d) q(X) r(CR eR f) sR 4, wherein
R a, R b, R c, R d, R eAnd R fBe H independently, C 1-4Alkyl (for example methyl), halogen (for example chlorine), cyano group, hydroxyl, C 1-4Alkoxyl group (for example methoxyl group) or C 1-4Alkoxy carbonyl (for example ethoxy carbonyl), or R aR b, R cR dOr R eR fCan encircle in conjunction with forming the optional 3-8 unit that contains aerobic, sulphur or nitrogen-atoms,
X is (CO), (CO) O, O (CO), O, S (O) tWherein t is 0,1 or 2, NH or N (C 1-6) alkyl,
P, r and s are 0 or 1,
Q is 0,1 or 2,
R 4Be C 1-6Alkyl (for example methyl, ethyl, sec.-propyl, normal-butyl, the tertiary butyl) is optionally replaced by one, two or three substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine), cyano group or hydroxyl, C 1-4Alkoxyl group (C 1-4) alkyl (for example methoxymethyl, ethoxyethyl group), C 1-4Alkoxyl group-(C 1-4) alkoxyl group (C 1-4) alkyl (for example methoxy ethoxy methyl), benzyloxy (C 1-4) alkyl (for example benzyloxy methyl), C 2-6Alkene oxygen base (for example allyloxy) ,-S (O) x(C 1-6) alkyl, wherein x is 0,1 or 2 and alkyl is optional is replaced by halogen (fluorine particularly, for example 2,2,2-trifluoro ethylmercapto group), single-or two-(C 1-6) alkylamino (for example N-methylamino, N, N-dimethylamino) or three (C 1-4) alkyl silyl (for example trimethyl silyl), or
R 4Be C 2-6Thiazolinyl (for example vinyl, allyl group) is optionally replaced by one, two or three substituting groups, and described substituting group is independently selected from halogen (for example chlorine), cyano group, hydroxyl, C 1-6Alkoxyl group (for example methoxyl group), C 1-6Alkyl-carbonyl (for example ethanoyl), C 1-6Alkoxy carbonyl (for example methoxycarbonyl), optional by C 1-4The phenyl that alkoxyl group replaces, or
R 4Be C 3-6Cycloalkyl (for example cyclopropyl, cyclopentyl, cyclohexyl), C 5-6Cycloalkenyl group (for example cyclopentenyl, cyclohexenyl), aryl (for example phenyl, naphthyl), heteroaryl (5 yuan of heteroaryls, for example pyrryl, furyl, thienyl, pyrazolyl, imidazolyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, triazolyl ， oxadiazole base, thiadiazolyl group, tetrazyl; 6-unit heteroaryl, pyridyl for example, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl), or part or complete saturated cyclic group, optional one or two heteroatoms that is independently selected from N, O or S (pyrrolidyl for example that contains, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, dioxolanyl, morpholinyl, thiadiazine base, 1,2,3, the 4-tetralyl, 2, the 3-dihydro benzo furyl)
Described aryl, heteroaryl or part or complete saturated cyclic group are optional to be replaced by one, two or three substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl, n-pentyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example difluoro-methoxy, trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group ,-SF 5,-S (O) x(C 1-6) alkyl, wherein x is 0,1 or 2 and alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyl) ,-OSO by halogen 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyloxy) ,-CONR by halogen xR y,-CON (OR x) R y,-COR x,-CO 2R x,-CR x=NR y,-NR xR y,-NR xCOR y,-NR xCO 2R y,-SO 2NR xR yOr-NR xSO 2R z, R wherein zBe the optional C that is replaced by halogen 1-8Alkyl, R xAnd R yBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), or
R 2And R 3Can be in conjunction with forming saturated or undersaturated 5-or 6-unit ring, described ring is optional to contain aerobic or sulphur atom (Pyrrolidine base for example, thiazolidyl, piperidyl, morpholinyl, thio-morpholinyl, 2,5-pyrrolin base) and optional replaced, described substituting group is halogen (a for example chlorine), C by one, two or three substituting groups 1-4Alkyl (for example methyl, ethyl) or single-or two-(C 1-4) alkyl amino-carbonyl, or optional contain nitrogen-atoms (for example piperazinyl), optional by C on nitrogen-atoms 1-4Alkyl replaces, described C 1-4Alkyl is optional by halogen, C 1-6Alkoxyl group or cyano group replace, or are optionally replaced by phenyl, and described phenyl is optional by nitro, C 1-4Alkyl, halo (C 1-4) alkyl (for example trifluoromethyl), C 1-4Alkyl-carbonyl (for example ethanoyl) or heteroaryl (for example pyridyl) replace, or
R 2And R 3Can be in conjunction with forming 6,6-unit saturated bicyclic (for example Decahydroisoquinolinpreparation); Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part are optional to be substituted;
L is O or S; With
N is 0,1 or 2.
Compound (1) particularly importantly, wherein Ar is a phenyl, is optionally replaced by one, two, three, four or five substituting groups, described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl (C 1-6) alkyl (for example phenmethyl), aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) u(C 1-6) alkyl, wherein u is 0,1 or 2 and alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyl) ,-OSO by halogen 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example three fluoro-sulfonyloxy methyl oxygen bases) ,-CONR by halogen uR v,-COR u,-CO 2R u,-CR u=NR v,-NR uR v,-NR uCOR v,-NR uCO 2R v,-SO 2NR uR vOr-NR uSO 2R w, R wherein wBe the optional C that is replaced by halogen 1-6Alkyl, R uAnd R vBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), or ,-CONR uR vOr-SO 2NR uR vSituation under, can be in conjunction with forming 5-or 6-unit ring, described ring contains a nitrogen-atoms, a sulphur atom, a saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part are optional to be substituted.
More importantly be compound (1), wherein Ar is a phenyl, optional is replaced by one, two or three substituting groups, and described substituting group is independently selected from halogen, chlorine or bromine particularly, cyano group, and C 1-6Alkyl, particularly methyl.The particularly important is wherein that Ar is 3,5-dichlorophenyl, 3,4,5-trimethylphenyl, 4-bromo-3,5-3,5-dimethylphenyl or 4-cyano group-3, the compound of 5-3,5-dimethylphenyl.
The more important thing is compound (1), wherein Ar is a pyridyl, optional is replaced by one, two, three, four or five substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl (C 1-6) alkyl (for example phenmethyl), aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) u(C 1-6) alkyl, wherein u is 0,1 or 2 and alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyl) ,-OSO by halogen 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example three fluoro-sulfonyloxy methyl oxygen bases) ,-CONR by halogen uR v,-COR u,-CO 2R u,-CR u=NR v,-NR uR v,-NR uCOR v,-NR uCO 2R v,-SO 2NR uR vOr-NR uSO 2R w, R wherein wBe the optional C that is replaced by halogen 1-6Alkyl, R uAnd R vBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), or ,-CONR uR vOr-SO 2NR uR vSituation under, can be in conjunction with forming 5-or 6-unit ring, described ring contains a nitrogen-atoms, a sulphur atom, a saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned arbitrary alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part are optional to be substituted.
More importantly be compound (1), wherein Ar is a pyridyl, and is optional by particularly chlorine replacement of halogen.Particularly importantly wherein pyridyl connects via the 3-position, as the compound of 5-chloropyridine-3-base.
More importantly be compound (1), wherein Ar is a benzothiazolyl, optional is replaced by one, two, three, four or five substituting groups, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl-(C 1-6) alkyl (for example phenmethyl), aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) u(C 1-6) alkyl, wherein u be 0,1 or 2 and the optional halogen of alkyl be substituted (particularly fluorine, for example trifluoromethyl sulfonyl) ,-OSO 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyloxy) ,-CONR by halogen uR v,-COR u,-CO 2R u,-CR u=NR v,-NR uR v,-NR uCOR v,-NR uCO 2R v,-SO 2NR uR vOr-NR uSO 2R w, R wherein wBe the optional C that is replaced by halogen 1-6Alkyl, R uAnd R vBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), or ,-CONR uR vOr-SO 2NR uR vSituation under, can be in conjunction with forming 5-or 6-unit ring, described ring contains a nitrogen-atoms, a sulphur atom, a saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl or part are optional to be substituted.
More importantly be compound (1), wherein Ar is a benzothiazolyl, and is optional by particularly chlorine replacement of halogen.Particularly importantly wherein benzothiazolyl connects via the 6-position, as the compound of benzothiazole-6-base.
Compound (1) particularly importantly, wherein Ar is a dibenzofuran group, is optionally replaced by one, two, three, four or five substituting groups, described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl-(C 1-6) alkyl (for example phenmethyl), aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) u(C 1-6) alkyl, wherein u is 0,1 or 2 and alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl-alkylsulfonyl) ,-OSO by halogen 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyloxy) ,-CONR by halogen uR v,-COR u,-CO 2R u,-CR u=NR v,-NR uR v,-NR uCOR v,-NR uCO 2R v,-SO 2NR uR vOr-NR uSO 2R w, R wherein wBe the optional C that is replaced by halogen 1-6Alkyl, R uAnd R vBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), or ,-CONR uR vOr-SO 2NR uR vSituation under, can be in conjunction with forming 5-or 6-unit ring, described ring contains a nitrogen-atoms, a sulphur atom, a saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl base or part are optional to be substituted.
Compound (1) particularly importantly, wherein Ar is a dibenzofuran group, is optionally replaced by one, two or three substituting groups, described substituting group is independently selected from halogen, particularly chlorine or bromine, and C 1-6Alkyl, particularly methyl.Particularly importantly wherein dibenzofuran group connects via the 2-position, as the compound of diphenylene-oxide-2-base.
Compound (1) particularly importantly, wherein Ar is a quinolyl, is optionally replaced by one, two, three, four or five substituting groups, described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine, iodine), cyano group, nitro, azido-, C 1-6Alkyl (for example methyl), halo (C 1-6) alkyl (for example trifluoromethyl), C 3-6Cycloalkyl, C 3-6Cycloalkyl (C 1-4) alkyl, C 2-6Thiazolinyl (for example allyl group), halo (C 2-6) thiazolinyl, C 2-6Alkynyl (for example propargyl), halo (C 2-6) alkynyl, C 1-6Alkoxyl group (for example methoxyl group), halo (C 1-6) alkoxyl group (for example trifluoromethoxy), C 2-6Alkene oxygen base (for example allyloxy), halo (C 2-6) alkene oxygen base, C 2-6Alkynyloxy group (for example alkynes propoxy-), halo (C 2-6) alkynyloxy group, aryl (for example phenyl), aryloxy (for example phenoxy group), aryl (C 1-6) alkyl (phenmethyl for example, aryl (C 1-6) alkoxyl group (for example benzyloxy), heteroaryl (for example pyridyl), heteroaryloxy (for example pyridyloxy), heteroaryl (C 1-6) alkyl (for example pyridylmethyl), heteroaryl (C 1-6) alkoxyl group (for example pyridyl methoxyl group) ,-SF 5,-S (O) u(C 1-6) alkyl, wherein u is 0,1 or 2 and alkyl is optional is replaced (particularly fluorine, for example trifluoromethyl sulfonyl) ,-OSO by halogen 2(C 1-4) alkyl, wherein alkyl is optional is replaced (particularly fluorine, for example three fluoro-sulfonyloxy methyl oxygen bases) ,-CONR by halogen uR v,-COR u,-CO 2R u,-CR u=NR v,-NR uR v,-NR uCOR v,-NR uCO 2R v,-SO 2NR uR vOr-NR uSO 2R w, R wherein wBe the optional C that is replaced by halogen 1-6Alkyl, R uAnd R vBe H or the optional C that is replaced by halogen independently 1-6Alkyl (for example-NHCOCF 3Or-N (CH 3) 2), or ,-CONR uR vOr-SO 2NR uR vSituation under, can be in conjunction with forming 5-or 6-unit ring, described ring contains a nitrogen-atoms, a sulphur atom, a saturated carbon atom and an optional Sauerstoffatom; Wherein aforementioned any alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or heteroaryl base or part are optional to be substituted.
Compound (1) particularly importantly, wherein Ar is a quinolyl, is optionally replaced by one, two or three substituting groups, described substituting group is independently selected from halogen, particularly fluorine, chlorine or bromine, C 1-4Alkyl, particularly methyl, halo (C 1-4) alkyl, particularly trifluoromethyl, aryl, particularly phenyl, and heteroaryl, particularly pyridyl.Preferred compound (1) is these compounds, wherein quinolyl connects via the 6-position, 3-bromoquinoline-6-base for example, 3-chloroquinoline-6-base, 3-fluorine quinoline-6-base, 3,8-two bromoquinolines-6-base, 3-bromo-8-chloroquinoline-6-base, 3-bromo-8-toluquinoline-6-base, 3-phenylquinoline-6-base or 3-pyridin-4-yl quinoline-6-base.Most preferred (1) is that wherein Ar is 3-bromoquinoline-6-base, 3, and 8-two bromoquinolines-6-base, 3-bromo-8-chloroquinoline-6-base or 3-bromo-8-toluquinoline-6-base.
Another organizes preferred compound (1) is these, wherein Ar is 3,8-difluoro-quinoline-6-base, 3-fluoro-8-chloroquinoline-6-base, 3-fluoro-8-bromoquinoline-6-base, 3-fluoro-8-iodine quinoline-6-base, 3-fluoro-8-toluquinoline-6-base, 3,8-dichloroquinoline-6-base, 3-chloro-8-fluorine quinoline-6-base, 3-chloro-8-bromoquinoline-6-base, 3-chloro-8-iodine quinoline-6-base, 3-chloro-8-toluquinoline-6-base, 3,8-bromoquinoline-6-base, 3-bromo-8-chloroquinoline-6-base, 3-bromo-8-fluorine quinoline-6-base, 3-bromo-8-iodine quinoline-6-base, 3-bromo-8-toluquinoline-6-base, 3,8-iodine quinoline-6-base, 3-iodo-8-chloroquinoline-6-base, 3-iodo-8-bromoquinoline-6-base, 3-iodo-8-fluorine quinoline-6-base or 3-iodo-8-toluquinoline-6-base.
Another organize particularly preferred compound (1) be those wherein Ar be the compound of 8-halogenated quinoline-6-base or 8-toluquinoline-6-base.
R 1Methyl normally.
R 2Normally H or methyl, most preferably H.
R 2Preferably also comprise C 1-8Alkyl, C 3-4Cycloalkyl, C 2-8Thiazolinyl and cyano group (C 1-4) alkyl.
R 2Also comprise C 1-4Alkoxyl group (C 1-4) alkyl, particularly C 1-4Alkoxy methyl and benzyloxy methyl, wherein an optional alkoxy substituent, for example the methoxyl group substituting group of being loaded with of the benzyl ring of phenmethyl.
Compound (1) particularly importantly is wherein at R 3Definition in, p is 1, q, r and s are 0, R aAnd R bAll be methyl or R aBe methyl, R bBe cyano group.R wherein particularly importantly 3It is the tertiary butyl, 1,1,1-three fluoro-2-methyl-prop-2-bases, 2-cyano group third-2-base, 1-methoxyl group-2-methyl-prop-2-base, 1-methylthio group-2-methyl-prop-2-base, 1-methoxyl group-3-methyl fourth-3-base, 2-cyano group-1-methoxy propyl-2-base, the compound (1) of 2-methoxycarbonyl third-2-base or 2-methylamino carbonyl third-2-base.R wherein most preferably 3Be the tertiary butyl, the compound (1) of 1-methoxyl group-2-methyl-prop-2-base or 2-cyano group-1-methoxy propyl-2-base.
More importantly compound is R wherein 3It is the compound (1) of 2-methylol-1-methoxy propyl-2-base or 1-methoxyl group-2-methoxymethyl third-2-base.
L is O normally; N normally 0.
Part of compounds of the present invention is illustrated among the following table 1-366.
Part of compounds in the following table provides fusing point (mp) and/or characteristic molion (M for example +, [M+1] +) value.Spectrum (1H NMR) data are provided in embodiment 1-13E in addition, in embodiment 14, provide biological activity simultaneously.
Table 1
Compound in the table 1 is general formula (a 1) compound, and wherein Ar is 3, and 5-dichlorophenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has the implication that provides in the table.
Compound number R 2 R 3
1 H CH 3
2 CH 3 CH 3
3 H C 2H 5
4 C 2H 5 C 2H 5
5 H Third-2-base
6 CH 3 Third-2-base
7 Third-2-base Third-2-base
8 CH 3 Normal-butyl
9 H Fourth-2-base
10 H 2-methyl-third-1-base
11 2-methyl-third-1-base 2-methyl-third-1-base
12 H Uncle-C 4H 9
13 CH 3 Uncle-C 4H 9
14 H Penta-2-base
15 H Penta-3-base
16 H 2-methyl-Ding-2-base
17 H 3-methyl-Ding-1-base
18 H 3-methyl-penta-2-base
19 H 4-methyl-penta-2-base
20 H 3,3-dimethyl-Ding-2-base
21 H The 2-methyl-oneself-2-is own
22 H 2,4-dimethyl-penta-2-base
23 H 2,4,4-trimethylammonium-Ding-2-base
24 H 2,4,4-trimethylammonium-penta-2-base
25 H Cl-just-C 3H 6-
26 H Cl-CH 2(CH 3) 2C-
27 H F 3C(CH 3) 2C-
28 H NC-CH 2-
29 CH 3 NC-CH 2-
30 NC-CH 2- NC-CH 2-
31 H (NC) 2CH-
32 H NC-C 2H 4-
33 CH 3 NC-C 2H 4-
34 NC-C 2H 4- NC-C 2H 4-
35 H (CH 3) 2C(CN)-
36 H C 2H 5(CH 3)C(CN)-
37 H (C 2H 5) 2C(CN)-
38 H (CH 3) 2CH(CH 3)C(CN)-
39 H HO-CH 2(CH 3) 2C-
40 H HO-C 2H 4(CH 3) 2C-
41 H 1-hydroxyl-2-(methylol)-third-2-base
42 H 1-hydroxyl-2-(methoxymethyl) third-2-base
43 H 1-methoxyl group-2-(methoxymethyl) third-2-base
44 H 1-hydroxyl-2-(methylol)-Ding-2-base
45 C 2H 5OC 2H 4- C 2H 5OC 2H 4-
46 CH 3 (CH 3O) 2CHCH 2-
47 H CH 3O-CH 2(CH 3) 2C-
48 H CH 3O-C 2H 4(CH 3) 2C-
49 H C 2H 5O-C 2H 4(CH 3) 2C-
50 H CH 3S-CH 2(CH 3) 2C-
51 H NC-(CH 3O)CH-
52 H CH 3OCH 2(CH 3)C(CN)- M +363
53 H CH 3SCH 2(CH 3)C(CN)- M +379
54 H CH 3(CO)(CH 3) 2C-
55 H CH 3CHBr(CO)(CH 3) 2C-
56 H CH 3(CO)(OH)CH(CH 3) 2C-
57 H CH 3OC 2H 4(CO)(CH 3) 2C-
58 H CH 3(CO)CH 2(CH 3) 2C-
59 H CH 3O(CO)(CH 3)CH-
60 H CH 3O(CO)(CH 3) 2C-
61 H C 2H 5O(CO)C 2H 4-
62 H CH 3NH(CO)(CH 3) 2C-
63 H (CH 3) 2N(CO)(CH 3) 2C-
64 H (CH 3) 3SiCH 2-
65 H Uncle-C 4H 9(CH 3) 2SiO-CH 2(CH 3) 2C-
66 H Uncle-C 4H 9(CH 3) 2SiO-C 2H 4(CH 3) 2C-
67 H 4-FPhCH 2OCH 2(CH 3) 2C-
68 H C 2H 5OCH 2(CH 3) 2C-
69 H CH 3OCH 2CH 2O(CH 3) 2C-
70 H CH 2＝CHCH 2-
71 CH 2＝CHCH 2- CH 2＝CHCH 2-
72 H CH 2＝C(CH 3)CH 2-
73 H CH 2＝CH(CH 3)CH-
74 H CH 2＝CH(CH 3) 2C-
75 H CH 3(CO)CH＝CH-
76 CH 3 CH 3(CO)CH＝CH-
77 H Penta-3-alkene-2-base
78 H The 2-methyl-oneself-3-alkene-2-base (E)
79 H The 2-methyl-oneself-3-alkene-2-base (Z)
80 H 2-methyl-penta-4-alkene-3-ketone-2-base
81 H CH 3O(CO)CH＝(Cl)C(CH 3) 2C-
82 H C 6H 5-C(CH 3)＝CH(CH 3) 2C-
83 CH 2＝CHCH 2- CH 2＝CHCH 2OC 2H 4-
84 H CH≡CCH 2-
85 CH 3 CH≡CCH 2-
86 H Ring third-1-base
87 NC-C 2H 4- Ring third-1-base
88 Ring third-1-base Ring third-1-base
89 H 1-cyano group-ring third-1-base
90 H 2-cyano group-ring third-1-base
91 H 1-methoxycarbonyl-ring third-1-base
92 H 1-[N, N-dimethylamino carbonyl]-ring third-1-base
93 H 1-[N-methyl-N-methoxyl group-aminocarboxyl]-ring third-1-base
94 H 1-cyano group-1-cyclopropyl-second-1-base
95 H Ring penta-1-base
96 H 1-cyano group-ring penta-1-base
97 H Hexamethylene-1-base
98 CH 2＝CHCH 2- Hexamethylene-1-base
99 H 4-cyano group-hexamethylene-1-base
100 H 1-cyano group-4-methyl-cyclohexyl-1-base
101 H The 4-tertiary butyl-1-cyano group-hexamethylene-1-base
102 H 2-methyl-3-cyano group tetrahydrofuran (THF)-3-base
103 H The 5-methyl isophthalic acid, 3-dioxolane-5-base
104 H 5-ethyl-1,3-dioxolane-5-base
105 H 3,5-dimethyl-1,3-dioxolane-5-base
106 H N-ethoxy carbonyl-piperidin-4-yl
107 H Morpholinyl
108 H Hexamethylene-1-base-methyl
109 H 4-cyano group-cyclopentenes-3-base
110 H The 5-tertiary butyl-2H-1,3,4-thiadiazine-2-base
111 H 2-(tetrahydrobenzene-1-yl)-second-1-base
112 H Furans-2-base
113 H 5-methoxycarbonyl-furans-2-base
114 H Thiophene-2-base
115 H 2-methoxycarbonyl-thiene-3-yl-
116 H 4-methoxycarbonyl-thiene-3-yl-
117 H Oxazole-2-base
118 H 5-methyl-isoxazole-3-bases
119 H 4-cyano group-3-methyl-isoxazole-5-bases
120 H Thiazol-2-yl
121 H 5-ethylmercapto group-1,3,4-thiadiazoles-2-base
122 H Furans-2-ylmethyl
123 H Cyano group furans-1-ylmethyl
124 H Thiophene-2-ylmethyl
125 H C 6H 5-
126 H 2-Cl-C 6H 4-
127 H 2-I-C 6H 4-
128 H 2-NC-C 6H 4-
129 H 3-CF 3-C 6H 4-
130 H 3-CH 3S-C 6H 4-
131 H 3-CH 3O(CO)-C 6H 4-
132 H 4-Cl-C 6H 4-
133 H 4-F-C 6H 4-
134 H 4-CF 3O-C 6H 4-
135 H 4-(C 2H 5) 2N-C 6H 4-
136 H 4-(N-methyl-N-ethanoyl-amino)-phenyl
137 H The 2,4 dichloro benzene base
138 H 4-methoxyl group-2-aminomethyl phenyl
139 H 3, the 4-dichlorophenyl
140 H 3-chloro-4-fluorophenyl
141 H 2, the 5-difluorophenyl
142 H 5-fluoro-2-aminomethyl phenyl
143 H 5,6,7,8-naphthane-2-base
144 H 2,3-Dihydrobenzofuranes-5-base-methyl
145 H 5-cyano group-4,6-dimethoxy-pyridine-2-base
146 H 2,6-dimethoxy-pyridin-3-yl
147 H 6-chloro-pyridazine-3-base
148 H 4,6-dimethoxy-pyrimidine-2-base
149 H 2-chloro-5-fluoro-pyrimidine-6-base
150 H C 6H 5CH 2-
151 CH 3 C 6H 5CH 2-
152 H 2-F-C 6H 4CH 2-
153 H 2-Cl-C 6H 4CH 2-
154 CH 3 2-Cl-C 6H 4CH 2-
155 H 2-NO 2-C 6H 4CH 2-
156 H 2-CH 3-C 6H 4CH 2-
157 H 2-CH 3O-C 6H 4CH 2-
158 H 2-CHF 2O-C 6H 4CH 2-
159 H 2-CH 3S-C 6H 4CH 2-
160 H 2-CF 3S-C 6H 4CH 2-
161 H 3-Cl-C 6H 4CH 2-
162 H 3-I-C 6H 4CH 2-
163 H 3-CH 3-C 6H 4CH 2-
164 H 3-CH 3O-C 6H 4CH 2-
165 H 4-F-C 6H 4CH 2-
166 H 4-Cl-C 6H 4CH 2-
167 H 4-CH 3-C 6H 4CH 2-
168 H 4-CF 3-C 6H 4CH 2-
169 H 4-CH 3O-C 6H 4CH 2-
170 H 4-CF 3O-C 6H 4CH 2-
171 H 2,6-two-F-C 6H 3CH 2-
172 3-methyl-Ding-2-alkene-1-base 2,5-two-F-C 6H 3CH 2-
Figure G05840077020070525D000221
Figure G05840077020070525D000231
Table 2
The compound of table 2 is general formula (1) compounds, and wherein Ar is 3, and 5-dibromo phenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 2 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 2 is 3, and 5-dibromo phenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 2 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 2 is 3, and 5-dibromo phenyl rather than 3,5-dichlorophenyl.
Table 3
The compound of table 3 is general formula (1) compounds, and wherein Ar is 3, and 5-difluorophenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 3 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 3 is 3, and 5-difluorophenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 3 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 3 is 3, and 5-difluorophenyl rather than 3,5-dichlorophenyl.
Table 4
The compound of table 4 is general formula (1) compounds, and wherein Ar is 3, and 5-3,5-dimethylphenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 4 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 4 is 3, and 5-3,5-dimethylphenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 4 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 4 is 3, and 5-3,5-dimethylphenyl rather than 3,5-dichlorophenyl.
Table 5
The compound of table 5 is general formula (1) compounds, and wherein Ar is a 3-chloro-5-aminomethyl phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 5 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 5 is 3-chloro-5-aminomethyl phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 5 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 5 is 3-chloro-5-aminomethyl phenyl rather than 3, and the 5-dichlorophenyl.
Table 6
The compound of table 6 is general formula (1) compounds, and wherein Ar is 3,5-two (trifluoromethyl) phenyl, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 6 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 6 is 3, and 5-two (trifluoromethyl) phenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 6 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 6 is 3, and 5-two (trifluoromethyl) phenyl rather than 3,5-dichlorophenyl.
Table 7
The compound of table 7 is general formula (1) compounds, and wherein Ar is 3-ethyl-5-aminomethyl phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 7 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 7 is 3-ethyl-5-aminomethyl phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 7 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 7 is 3-ethyl-5-aminomethyl phenyl rather than 3, and the 5-dichlorophenyl.
Table 8
The compound of table 8 is general formula (1) compounds, and wherein Ar is 3, and 5-Dimethoxyphenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 8 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 8 is 3, and 5-Dimethoxyphenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 8 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 8 is 3, and 5-Dimethoxyphenyl rather than 3,5-dichlorophenyl.
Table 9
The compound of table 9 is general formula (1) compounds, and wherein Ar is a 3-chloro-5-p-methoxy-phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 9 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 9 is 3-chloro-5-p-methoxy-phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 9 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 9 is 3-chloro-5-p-methoxy-phenyl rather than 3, and the 5-dichlorophenyl.
Table 10
The compound of table 10 is general formula (1) compounds, and wherein Ar is 3-cyano group-5-p-methoxy-phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 10 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 10 is 3-cyano group-5-p-methoxy-phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 10 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 10 is 3-cyano group-5-p-methoxy-phenyl rather than 3, and the 5-dichlorophenyl.
Table 11
The compound of table 11 is general formula (1) compounds, and wherein Ar is 3,4, the 5-trichlorophenyl, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 11 is identical with the compound 1 of table 1, and Ar is 3,4,5-trichlorophenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 11 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 11 is 3,4, and 5-trichlorophenyl rather than 3,5-dichlorophenyl.
Table 12
The compound of table 12 is general formula (1) compounds, and wherein Ar is 3,5-two bromo-4-aminomethyl phenyls, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 12 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 12 is 3, and 5-two bromo-4-aminomethyl phenyls rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 12 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 12 is 3, and 5-two bromo-4-aminomethyl phenyls rather than 3,5-dichlorophenyl.
Table 13
The compound of table 13 is general formula (1) compounds, and wherein Ar is 3,4, and 5-trimethylphenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 13 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 13 is 3,4, and 5-trimethylphenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 13 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 13 is 3,4, and 5-trimethylphenyl rather than 3,5-dichlorophenyl.
The preparation of 2-(3,4,5-trimethylammonium phenoxy group)-2-methylthio group-N-(2-methyl-third-2-yl) ethanamide (compound number 12 of table 13) is described among the embodiment 2 the 73rd page.
The compound 12,52,70,120,124 of table 13 and 150 1H NMR characteristic provides at the 76th page.
Table 14
The compound of table 14 is general formula (1) compounds, and wherein Ar is 3,5-dimethyl-4-chloro-phenyl-, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 14 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 14 is 3, and 5-dimethyl-4-chloro-phenyl-rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 14 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 14 is 3, and 5-dimethyl-4-chloro-phenyl-rather than 3,5-dichlorophenyl.
Table 15
The compound of table 15 is general formula (1) compounds, and wherein Ar is 3,5-dimethyl-4-bromophenyl, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 15 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 15 is 3, and 5-dimethyl-4-bromophenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 15 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 15 is 3, and 5-dimethyl-4-bromophenyl rather than 3,5-dichlorophenyl.
Compound number R 2 R 3
52 H CH 3OCH 2(CH 3)C(CN)- [M+2] +403
Table 16
The compound of table 16 is general formula (1) compounds, and wherein Ar is 3,5-dimethyl-4-methylthio group phenyl, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 16 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 16 is 3, and 5-dimethyl-4-methylthio group phenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 16 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 16 is 3, and 5-dimethyl-4-methylthio group phenyl rather than 3,5-dichlorophenyl.
Table 17
The compound of table 17 is general formula (1) compounds, and wherein Ar is a 4-cyano group-3, and 5-3,5-dimethylphenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 17 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 17 is a 4-cyano group-3, and 5-3,5-dimethylphenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 17 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 17 is a 4-cyano group-3, and 5-3,5-dimethylphenyl rather than 3,5-dichlorophenyl.
Table 18
The compound of table 18 is general formula (1) compounds, and wherein Ar is 3, and 4-dichlorophenyl, n are 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 18 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 18 is 3, and 4-dichlorophenyl rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 18 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 18 is 3, and 4-dichlorophenyl rather than 3,5-dichlorophenyl.
Table 19
The compound of table 19 is general formula (1) compounds, and wherein Ar is a 3-chloro-4-aminomethyl phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 19 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 19 is 3-chloro-4-aminomethyl phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 19 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 19 is 3-chloro-4-aminomethyl phenyl rather than 3, and the 5-dichlorophenyl.
Table 20
The compound of table 20 is general formula (1) compounds, and wherein Ar is 3-methyl-4-chloro-phenyl-, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 20 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 20 is 3-methyl-4-chloro-phenyl-rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 20 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 20 is 3-methyl-4-chloro-phenyl-rather than 3, and the 5-dichlorophenyl.
Table 21
The compound of table 21 is general formula (1) compounds, and wherein Ar is a 3-chloro-4-cyano-phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 21 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 21 is 3-chloro-4-cyano-phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 21 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 21 is 3-chloro-4-cyano-phenyl rather than 3, and the 5-dichlorophenyl.
Table 22
The compound of table 22 is general formula (1) compounds, and wherein Ar is 3-methyl-4-methylthio group phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 22 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 22 is 3-methyl-4-methylthio group phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 22 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 22 is 3-methyl-4-methylthio group phenyl rather than 3, and the 5-dichlorophenyl.
Table 23
The compound of table 23 is general formula (1) compounds, and wherein Ar is the 3-chloro-phenyl-, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 23 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 23 is 3-chloro-phenyl-rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 23 compound 2-237 with table 1 respectively is identical, except 3-chloro-phenyl-rather than 3 in the compound of table 23,5-dichlorophenyl.
Table 24
The compound of table 24 is general formula (1) compounds, and wherein Ar is the 3-trifluoromethyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 24 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 24 is 3-trifluoromethyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 24 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 24 is 3-trifluoromethyl rather than 3, and the 5-dichlorophenyl.
Table 25
The compound of table 25 is general formula (1) compounds, and wherein Ar is the 3-Trifluoromethoxyphen-l, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 25 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 25 is 3-Trifluoromethoxyphen-l rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 25 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 25 is 3-Trifluoromethoxyphen-l rather than 3, and the 5-dichlorophenyl.
Table 26
The compound of table 26 is general formula (1) compounds, and wherein Ar is the 3-nitrophenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 26 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 26 is 3-nitrophenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 26 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 26 is 3-nitrophenyl rather than 3, and the 5-dichlorophenyl.
Table 27
The compound of table 27 is general formula (1) compounds, and wherein Ar is the 3-acetylphenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 27 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 27 is 3-acetylphenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 27 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 27 is 3-acetylphenyl rather than 3, and the 5-dichlorophenyl.
Table 28
The compound of table 28 is general formula (1) compounds, and wherein Ar is the 4-chloro-phenyl-, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 28 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 28 is 4-chloro-phenyl-rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 28 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 28 is 4-chloro-phenyl-rather than 3, and the 5-dichlorophenyl.
Table 29
The compound of table 29 is general formula (1) compounds, and wherein Ar is the 4-bromophenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 29 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 29 is 4-bromophenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 29 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 29 is 4-bromophenyl rather than 3, and the 5-dichlorophenyl.
Table 30
The compound of table 30 is general formula (1) compounds, and wherein Ar is a p-methylphenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 30 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 30 is p-methylphenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 30 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 30 is p-methylphenyl rather than 3, and the 5-dichlorophenyl.
Table 31
The compound of table 31 is general formula (1) compounds, and wherein Ar is the 4-trifluoromethyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 31 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 31 is 4-trifluoromethyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 31 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 31 is 4-trifluoromethyl rather than 3, and the 5-dichlorophenyl.
Table 32
The compound of table 32 is general formula (1) compounds, and wherein Ar is the 4-tert-butyl-phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 32 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 32 is 4-tert-butyl-phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 32 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 32 is 4-tert-butyl-phenyl rather than 3, and the 5-dichlorophenyl.
Table 33
The compound of table 33 is general formula (1) compounds, and wherein Ar is the 4-cyano-phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 33 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 33 is 4-cyano-phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 33 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 33 is 4-cyano-phenyl rather than 3, and the 5-dichlorophenyl.
Table 34
The compound of table 34 is general formula (1) compounds, and wherein Ar is 4-five fluorine sulfenyl phenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 34 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 34 is 4-five fluorine sulfenyl phenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 34 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 34 is 4-five fluorine sulfenyl phenyl rather than 3, and the 5-dichlorophenyl.
Table 35
The compound of table 35 is general formula (1) compounds, and wherein Ar is the 4-nitrophenyl, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 35 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 35 is 4-nitrophenyl rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 35 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 35 is 4-nitrophenyl rather than 3, and the 5-dichlorophenyl.
Table 36
The compound of table 36 is general formula (1) compounds, and wherein Ar is indane-5-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 36 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 36 is indane-5-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 36 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 36 is indane-5-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3
12 H Uncle-C 4H 9 Oil
Table 37
The compound of table 37 is general formula (1) compounds, and wherein Ar is 1, dioxy cyclopentenes-5-base between the 3-benzo, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 37 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 37 is 1, and dioxy cyclopentenes between the 3-benzo-5-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 37 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 37 is 1, and dioxy cyclopentenes between the 3-benzo-5-base rather than 3,5-dichlorophenyl.
Table 38
The compound of table 38 is general formula (1) compounds, and wherein Ar is a 2-oxo-1,3-benzodioxole-5-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 38 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 38 is a 2-oxo-1, and 3-benzodioxole-5-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 38 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 38 is a 2-oxo-1, and 3-benzodioxole-5-base rather than 3,5-dichlorophenyl.
Table 39
The compound of table 39 is general formula (1) compounds, and wherein Ar is a 2-sulfo--1,3-benzodioxole-5-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 39 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 39 is a 2-sulfo--1, and 3-benzodioxole-5-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 39 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 39 is a 2-sulfo--1, and 3-benzodioxole-5-base rather than 3,5-dichlorophenyl.
Table 40
The compound of table 40 is general formula (1) compounds, and wherein Ar is 1,3-benzo oxa-thia cyclopentenes-5-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 40 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 40 is 1, and 3-benzo oxa-thia cyclopentenes-5-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 40 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 40 is 1, and 3-benzo oxa-thia cyclopentenes-5-base rather than 3,5-dichlorophenyl.
Table 41
The compound of table 41 is general formula (1) compounds, and wherein Ar is a 2-oxo-1,3-benzo oxa-thia cyclopentenes-5-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 41 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 41 is a 2-oxygen-1, and 3-benzo oxa-thia cyclopentenes-5-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 41 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 41 is a 2-oxygen-1, and 3-benzo oxa-thia cyclopentenes-5-base rather than 3,5-dichlorophenyl.
Table 42
The compound of table 42 is general formula (1) compounds, and wherein Ar is 1,3-benzo dithia cyclopentenes-5-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 42 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 42 is 1, and 3-benzo dithia cyclopentenes-5-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 42 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 42 is 1, and 3-benzo dithia cyclopentenes-5-base rather than 3,5-dichlorophenyl.
Table 43
The compound of table 43 is general formula (1) compounds, and wherein Ar is indenes-5-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 43 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 43 is indenes-5-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 43 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 43 is indenes-5-base rather than 3, and the 5-dichlorophenyl.
Table 44
The compound of table 44 is general formula (1) compounds, and wherein Ar is cumarone-5-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 44 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 44 is cumarone-5-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 44 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 44 is cumarone-5-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3
12 H Uncle-C 4H 9 Oil
189 H C 6H 5-(CH 3) 2C- 111-113℃
Table 45
The compound of table 45 is general formula (1) compounds, and wherein Ar is 2-phenyl cumarone-5-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 45 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 45 is 2-phenyl cumarone-5-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 45 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 45 is 2-phenyl cumarone-5-base rather than 3, and the 5-dichlorophenyl.
Table 46
The compound of table 46 is general formula (1) compounds, and wherein Ar is 3-methyl cumarone-5-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 46 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 46 is 3-methyl cumarone-5-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 46 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 46 is 3-methyl cumarone-5-base rather than 3, and the 5-dichlorophenyl.
Table 47
The compound of table 47 is general formula (1) compounds, and wherein Ar is the thionaphthene-5-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 47 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 47 is thionaphthene-5-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 47 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 47 is thionaphthene-5-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3
12 H Uncle-C 4H 9 Oil
Table 48
The compound of table 48 is general formula (1) compounds, and wherein Ar is the 9H-fluorenes-3-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 48 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 48 is 9H-fluorenes-3-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 48 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 48 is 9H-fluorenes-3-base rather than 3, and the 5-dichlorophenyl.
Table 49
The compound of table 49 is general formula (1) compounds, and wherein Ar is the 9-oxo-9H-fluorenes-3-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 49 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 49 is 9-oxo-9H-fluorenes-3-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 49 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 49 is 9-oxo-H-fluorenes-3-base rather than 3, and the 5-dichlorophenyl.
Table 50
The compound of table 50 is general formula (1) compounds, and wherein Ar is the diphenylene-oxide-2-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 50 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 50 is diphenylene-oxide-2-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 50 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 50 is diphenylene-oxide-2-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3
232 H 1-benzyloxy methyl-ring third-1-base [M+1] +449
230 H (CH 3) 2CH-CH 2(CH 3)C(CN)- [M+1] +398
228 H 4-CH 3O-C 6H 4-CH 2CH 2(CH 3)C(CN)- [M+2] +477
227 H 4-Cl-C 6H 4-CH 2(CH 3)C(CN)- [M+1] +466
The preparation of 2-(dibenzofuran group-2-oxygen)-2-methylthio group-N-(2-methyl-third-2-yl) ethanamide (compound 12 of table 50) is described among the embodiment 12 the 93rd page.
The compound 12,35,38,52,70,84,120,122,128,133 of table 50 and 189 1H NMR characteristic provides at the 94th and 95 page.
Table 51
The compound of table 51 is general formula (1) compounds, and wherein Ar is the 7-methyldiphenyl and the furans-2-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 51 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 51 is 7-methyldiphenyl and furans-2-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 51 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 51 is 7-methyldiphenyl and furans-2-base rather than 3, and the 5-dichlorophenyl.
Table 52
The compound of table 52 is general formula (1) compounds, and wherein Ar is the 8-chlorodiphenyl and the furans-2-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 52 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 52 is 8-chlorodiphenyl and furans-2-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 52 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 52 is 8-chlorodiphenyl and furans-2-base rather than 3, and the 5-dichlorophenyl.
Table 53
The compound of table 53 is general formula (1) compounds, and wherein Ar is the 9-chlorodiphenyl and the furans-2-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 53 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 53 is 9-chlorodiphenyl and furans-2-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 53 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 53 is 9-chlorodiphenyl and furans-2-base rather than 3, and the 5-dichlorophenyl.
Table 54
The compound of table 54 is general formula (1) compounds, and wherein Ar is the dibenzothiophene-2-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 54 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 54 is dibenzothiophene-2-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 54 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 54 is dibenzothiophene-2-base rather than 3, and the 5-dichlorophenyl.
Table 55
The compound of table 55 is general formula (1) compounds, and wherein Ar is 5,6,7 of a formula (A), 8-naphthane-2-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 55 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 55 is 5,6,7, and 8-naphthane-2-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 55 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 55 is 5,6,7, and 8-naphthane-2-base rather than 3,5-dichlorophenyl.
Compound number R 2 R 3
12 H Uncle-C 4H 9 Oil
Table 56
The compound of table 56 is general formula (1) compounds, and wherein Ar is the quinoline-6-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 56 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 56 is quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 56 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 56 is quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 57
The compound of table 57 is general formula (1) compounds, and wherein Ar is the 3-bromoquinoline-6-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 57 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 57 is 3-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 57 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 57 is 3-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
68 H C 2H 5OCH 2(CH 3) 2C- [M+2] +429 75-76.5
220 H (H 2C＝CHCH 2OCH 2)(CH 3) 2C- [M+2] +441 80-82
224 H C 6H 5CH 2OCH 2(CH 3) 2C- [M+2] +491 90-91
16 H 2-methyl-Ding-2-base [M+2] +399 103-104
229 H 2-Cl-C 6H 4-CH 2(CH 3)C(CN)- / 138-140
227 H 4-Cl-C 6H 4-CH 2(CH 3)C(CN)- / 77-79
226 H 4-F-C 6H 4-CH 2(CH 3)C(CN)- [M+]488 /
230 H (CH 3) 2CH-CH 2(CH 3)C(CN)- [M+2] +438 /
235 H 1-cyclopropyl-second-1-base / 106-108
236 H 2-fluoro-second-1-base / 104-106
237 H 2,2,2-three fluoro-1-methyl-second-1-bases / 163-166
The preparation of compound 48 2-of table 57 (3-bromoquinoline base-6-oxygen)-2-methylthio group-N-(1-methoxyl group-3-methyl fourth-3-yl) ethanamide is described among the embodiment 7 the 85th page.The compound 4,12,24,27,35,38,40,47,48,49,50,52,60,64,65,70,84,88,89,111,120,122,124,133,150,189 and 198 of table 57 1H NMR characteristic provides at the 86-89 page or leaf.
The preparation of compound 822-(the methylthio group)-2-of table 57 (3-bromoquinoline base-6-oxygen)-N-E-(4-phenyl-2-methylpent-3-alkene-2-yl) ethanamide is described among the embodiment 9 the 91st page.
The preparation of the compound 392-of table 57 (3-bromoquinoline base-6-oxygen)-2-(methylthio group)-N-(1-hydroxy-2-methyl third-2-yl) ethanamide with 1H NMR characteristic description in embodiment 11, the 93rd page.
Table 58
The compound of table 58 is general formula (1) compounds, and wherein Ar is 3-chloroquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 58 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 58 is 3-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 58 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 58 is 3-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.
The preparation of the compound 122-of table 58 (3-chloroquinoline base-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide is described among the embodiment 5 the 80th page.The compound 12,35,38,52,64,70,84,120,122,124,128,133,150,189 of table 58 1H NMR characteristic provides at the 82-83 page or leaf.
Table 58A
The compound of table 58A is general formula (a 1) compound, and wherein Ar is the 3-iodine quinoline-6-base of formula (A), and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 58A is identical with the compound 1 of table 1, except Ar in the compound 1 of table 58A is 3-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 58A, except Ar in the compound of table 58A is 3-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
12 H Uncle-C 4H 9 [M+1] +431 151-153
52 H CH 3OCH 2(CH 3)C(CN)- [M+1] +472 /
Table 59
The compound of table 59 is general formula (1) compounds, and wherein Ar is 3-fluorine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 59 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 59 is 3-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 59 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 59 is 3-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
The preparation of 2-(3-fluorine quinolyl-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 59) and compound 12 and 52 1H NMR characteristic-work being described in embodiment 8, the 89-91 pages or leaves.
Table 60
The compound of table 60 is general formula (1) compounds, and wherein Ar is 8-bromoquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 60 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 60 is 8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 60 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 60 is 8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
12 H Uncle-C 4H 9 122-125
52 H CH 3OCH 2(CH 3)C(CN)- 139-141
Table 60A
The compound of table 60A is general formula (a 1) compound, and wherein Ar is 8-chloroquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 60A is identical with the compound 1 of table 1, except Ar in the compound 1 of table 60A is 8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 60A, except Ar in the compound of table 60A is 8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 60B
The compound of table 60B is general formula (a 1) compound, and wherein Ar is 8-fluorine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 60B is identical with the compound 1 of table 1, except Ar in the compound 1 of table 60B is 8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 60B, except Ar in the compound of table 60B is 8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 60C
The compound of table 60C is general formula (a 1) compound, and wherein Ar is 8-iodine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 60C is identical with the compound 1 of table 1, except Ar in the compound 1 of table 60C is 8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 60C, except Ar in the compound of table 60C is 8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 61
The compound of table 61 is general formula (1) compounds, and wherein Ar is 3,8-two bromoquinolines-6-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 61 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 61 is 3, and 8-two bromoquinolines-6-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 61 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 61 is 3, and 8-two bromoquinolines-6-base rather than 3,5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
16 H 2-methyl-Ding-2-base 132-133
52 H CH 3OCH 2(CH 3)C(CN)- 139-142
50 H CH 3S-CH 2(CH 3) 2C- 141-143
68 H C 2H 5OCH 2(CH 3) 2C- 128.5-131.5
220 H (H 2C＝CHCH 2OCH 2)(CH 3) 2C- 97.5-101
224 H C 6H 5CH 2OCH 2(CH 3) 2C- 126-127
The preparation of 2-(3,8-dibromo quinolyl-6-oxygen)-2-methylthio group-N-(2-thienyl methyl) ethanamide (compound 124 of table 61) is described in 6, the 83 pages of embodiment.The compound 12,38,52,150 of table 61 and 211 1H NMR characteristic provides at the 85th and 85 page.
Table 62
The compound of table 62 is general formula (1) compounds, and wherein Ar is 3-bromo-8-chloroquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 62 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62 is 3-bromo-8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 62 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 62 is 3-bromo-8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
47 H CH 3O-CH 2(CH 3) 2C- [M+1] +449 125.5-127
12 H Uncle-C 4H 9 [M+1] +419 160-161
16 H 2-methyl-Ding-2-base [M+1] +433 /
50 H CH 3S-CH 2(CH 3) 2C- [M+1] +465 148-149
68 H C 2H 5OCH 2(CH 3) 2C- [M+1] +463 143-146
220 H (H 2C＝CHCH 2OCH 2)(CH 3) 2C- [M+1] +475 104-106
224 H C 6H 5CH 2OCH 2(CH 3) 2C- [M+1] +525 118-121
Table 62A
The compound of table 62A is general formula (a 1) compound, and wherein Ar is 3-bromo-8-iodine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62A is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62A is 3-bromo-8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62A, except Ar in the compound of table 62A is 3-bromo-8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
12 H Uncle-C 4H 9 171-172
Table 62B
The compound of table 62B is general formula (a 1) compound, and wherein Ar is 3-bromo-8-fluorine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62B is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62B is 3-bromo-8-fluorine quinoline-6-base-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62B, except Ar in the compound of table 62B is 3-bromo-8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
12 H Uncle-C 4H 9 158.5-159.5℃
52 H CH 3OCH 2(CH 3)C(CN)- Jelly
230 H (CH 3) 2CH-CH 2(CH 3)C(CN)- Jelly
Table 62C
The compound of table 62C is general formula (a 1) compound, and wherein Ar is 3-chloro-8-bromoquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62C is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62C is 3-chloro-8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62C, except Ar in the compound of table 62C is 3-chloro-8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62D
The compound of table 62D is general formula (a 1) compound, and wherein Ar is 3,8-dichloroquinoline-6-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62D is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62D is 3, and 8-dichloroquinoline-6-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62D, except Ar in the compound of table 62D is 3, and 8-dichloroquinoline-6-base rather than 3,5-dichlorophenyl.
Table 62E
The compound of table 62E is general formula (a 1) compound, and wherein Ar is 3-chloro-8-iodine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62E is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62E is 3-chloro-8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62E, except Ar in the compound of table 62E is 3-chloro-8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62F
The compound of table 62F is general formula (a 1) compound, and wherein Ar is 3-chloro-8-fluorine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62F is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62F is 3-chloro-8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62F, except Ar in the compound of table 62F is 3-chloro-8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62G
The compound of table 62G is general formula (a 1) compound, and wherein Ar is 3-fluoro-8-bromoquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62G is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62G is 3-fluoro-8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62G, except Ar in the compound of table 62G is 3-fluoro-8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62H
The compound of table 62H is general formula (a 1) compound, and wherein Ar is 3-fluoro-8-chloroquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62H is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62H is 3-fluoro-8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62H, except Ar in the compound of table 62H is 3-fluoro-8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62I
The compound of table 62I is general formula (a 1) compound, and wherein Ar is 3-fluoro-8-iodine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62I is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62I is 3-fluoro-8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62I, except Ar in the compound of table 62I is 3-fluoro-8-iodine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62J
The compound of table 62J is general formula (a 1) compound, and wherein Ar is 3,8-difluoro-quinoline-6-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62J is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62J is 3-chloro-8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62J, except Ar in the compound of table 62J is 3-chloro-8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62K
The compound of table 62K is general formula (a 1) compound, and wherein Ar is 3-iodo-8-bromoquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62K is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62K is 3-iodo-8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62K, except Ar in the compound of table 62K is 3-iodo-8-bromoquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62L
The compound of table 62L is general formula (a 1) compound, and wherein Ar is 3-iodo-8-chloroquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62L is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62L is 3-iodo-8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62L, except Ar in the compound of table 62L is 3-iodo-8-chloroquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62M
The compound of table 62M is general formula (a 1) compound, and wherein Ar is 3,8-dijodoxichinoline-6-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62M is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62M is 3, and 8-dijodoxichinoline-6-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62M, except Ar in the compound of table 62M is 3, and 8-dijodoxichinoline-6-base rather than 3,5-dichlorophenyl.
Table 62N
The compound of table 62N is general formula (a 1) compound, and wherein Ar is 3-iodo-8-fluorine quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62N is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62N is 3-iodo-8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62N, except Ar in the compound of table 62N is 3-iodo-8-fluorine quinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 62P
The compound of table 62P is general formula (a 1) compound, and wherein Ar is 8-toluquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 62P is identical with the compound 1 of table 1, except Ar in the compound 1 of table 62P is 8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 62P, except Ar in the compound of table 62P is 8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 63
The compound of table 63 is general formula (1) compounds, and wherein Ar is quinazoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 63 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 63 is quinazoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 63 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 63 is quinazoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 64
The compound of table 64 is general formula (1) compounds, and wherein Ar is isoquinoline 99.9-7-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 64 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 64 is isoquinoline 99.9-7-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 64 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 64 is isoquinoline 99.9-7-base rather than 3, and the 5-dichlorophenyl.
Table 65
The compound of table 65 is general formula (1) compounds, and wherein Ar is 3-phenylquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 65 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 65 is 3-phenylquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 65 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 65 is 3-phenylquinoline-6-base rather than 3, and the 5-dichlorophenyl.
The Mp of the compound 12 of table 65 and 1H NMR characteristic provides at the 93rd page.
Table 66
The compound of table 66 is general formula (1) compounds, and wherein Ar is 3-phenylmethylquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 66 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 66 is 3-phenylmethylquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 66 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 66 is 3-phenylmethylquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 67
The compound of table 67 is general formula (1) compounds, and wherein Ar is 7-bromo-naphthalene-2-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 67 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 67 is 7-bromo-naphthalene-2-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 67 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 67 is 7-bromo-naphthalene-2-base rather than 3, and the 5-dichlorophenyl.
Table 68
The compound of table 68 is general formula (1) compounds, and wherein Ar is 3-pyridin-4-yl-quinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 68 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 68 is 3-pyridin-4-yl-quinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 68 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 68 is 3-pyridin-4-yl-quinoline-6-base rather than 3, and the 5-dichlorophenyl.
The compound 12 of table 68, the preparation method of 2-(methylthio group)-2-(3-[4-pyridyl]-quinolyl-6-oxygen)-N-(2-methyl-prop-2-yl) ethanamide is described in 10, the 92 pages of embodiment.
Table 69
The compound of table 69 is general formula (1) compounds, and wherein Ar is isoquinoline 99.9-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 69 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 69 is isoquinoline 99.9-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 69 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 69 is isoquinoline 99.9-6-base rather than 3, and the 5-dichlorophenyl.
Table 70
The compound of table 70 is general formula (1) compounds, and wherein Ar is 5-chloropyridine-3-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 70 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 70 is 5-chloropyridine-3-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 70 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 70 is 5-chloropyridine-3-base rather than 3, and the 5-dichlorophenyl.
The compound 12 of table 70, the preparation of 2-(5-chloropyridine base-3-oxygen)-2-(methylthio group)-N-(2-methyl-prop-2-yl) ethanamide is described in 3, the 77 pages of embodiment.
The compound 12,50 of table 70 and 72 1H NMR characteristic provides at the 78th page.
Table 71
The compound of table 71 is general formula (1) compounds, and wherein Ar is 5-bromopyridine-3-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 71 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 71 is 5-bromopyridine-3-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 71 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 71 is 5-bromopyridine-3-base rather than 3, and the 5-dichlorophenyl.
Table 72
The compound of table 72 is general formula (1) compounds, and wherein Ar is 3-bromo-8-toluquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 72 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 72 is 3-bromo-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 72 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 72 is 3-bromo-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
12 H Uncle-C 4H 9 [M+2] +399 146-147
16 H 2-methyl-Ding-2-base [M+2] +413 129-132
47 H CH 3O-CH 2(CH 3) 2C- [M+2] +429 127-128.5
50 H CH 3S-CH 2(CH 3) 2C- [M+2] +445 130-131
52 H CH 3OCH 2(CH 3)C(CN)- [M+2] +440 116-118
68 H C 2H 5OCH 2(CH 3) 2C- [M+2] +443 /
220 H (H 2C＝CHCH 2OCH 2)(CH 3) 2C- [M+2] +455 /
224 H C 6H 5CH 2OCH 2(CH 3) 2C- [M+2] +505 112-113
Table 72A
The compound of table 72A is general formula (a 1) compound, and wherein Ar is 3-iodo-8-toluquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 72A is identical with the compound 1 of table 1, except Ar in the compound 1 of table 72A is 3-iodo-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 72A, except Ar in the compound of table 72A is 3-iodo-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3 Mp/℃
12 H Uncle-C 4H 9 148-150
52 H CH 3OCH 2(CH 3)C(CN)- 57-59
Table 72B
The compound of table 72B is general formula (a 1) compound, and wherein Ar is 3-chloro-8-toluquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 72B is identical with the compound 1 of table 1, except Ar in the compound 1 of table 72A is 3-chloro-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 72B, except Ar in the compound of table 72B is 3-chloro-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 72C
The compound of table 72C is general formula (a 1) compound, and wherein Ar is 3-fluoro-8-toluquinoline-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 72C is identical with the compound 1 of table 1, except Ar in the compound 1 of table 72C is 3-fluoro-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 72C, except Ar in the compound of table 72C is 3-fluoro-8-toluquinoline-6-base rather than 3, and the 5-dichlorophenyl.
Table 73
The compound of table 73 is general formula (1) compounds, and wherein Ar is 5,6-dichloropyridine-3-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 73 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 73 is 5, and 6-dichloropyridine-3-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 73 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 73 is 5, and 6-dichloropyridine-3-base rather than 3,5-dichlorophenyl.
Table 74
The compound of table 74 is general formula (1) compounds, and wherein Ar is 5-cyanopyridine-3-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 74 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 74 is 5-cyanopyridine-3-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 74 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 74 is 5-cyanopyridine-3-base rather than 3, and the 5-dichlorophenyl.
Table 75
The compound of table 75 is general formula (1) compounds, and wherein Ar is 5-ethynyl pyridine-3-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 75 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 75 is 5-ethynyl pyridine-3-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 75 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 75 is 5-ethynyl pyridine-3-base rather than 3, and the 5-dichlorophenyl.
Table 76
The compound of table 76 is general formula (1) compounds, and wherein Ar is 5-vinyl pyridine-3-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 76 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 76 is 5-vinyl pyridine-3-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 76 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 76 is 5-vinyl pyridine-3-base rather than 3, and the 5-dichlorophenyl.
Table 77
The compound of table 77 is general formula (1) compounds, and wherein Ar is 2,6-dichloropyridine-4-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 77 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 77 is 2, and 6-dichloropyridine-4-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 77 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 77 is 2, and 6-dichloropyridine-4-base rather than 3,5-dichlorophenyl.
Table 78
The compound of table 78 is general formula (1) compounds, and wherein Ar is benzothiazole-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 78 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 78 is benzothiazole-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 78 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 78 is benzothiazole-6-base rather than 3, and the 5-dichlorophenyl.
The preparation of 2-(benzothiazolyl-6-oxygen)-2-(methylthio group)-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 78) is described in 4, the 78 pages of embodiment, compound 12,35,52,70,133,189 1H NMR characteristic description is in the 79-80 page or leaf.
Table 79
The compound of table 79 is general formula (1) compounds, and wherein Ar is benzothiazole-6-base, and n is 0, and L is O, R 1Be ethyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 79 is identical with the compound 1 of table 78, except R in the compound 1 of table 79 1Be ethyl rather than methyl.Similarly, the compound 2-237 of the table 79 compound 2-237 with table 78 respectively is identical, except R in the compound of table 79 1Be ethyl rather than methyl.
Table 80
The compound of table 80 is general formula (1) compounds, and wherein Ar is 2-bromo benzothiazole-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 80 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 80 is 2-bromo benzothiazole-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 80 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 80 is 2-bromo benzothiazole-6-base rather than 3, and the 5-dichlorophenyl.
Table 81
The compound of table 81 is general formula (1) compounds, and wherein Ar is 2-chloro benzothiazole-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 81 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 81 is 2-chloro benzothiazole-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 81 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 81 is 2-chloro benzothiazole-6-base rather than 3, and the 5-dichlorophenyl.
Table 82
The compound of table 82 is general formula (1) compounds, and wherein Ar is 2-methylamino benzo thiazole-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 82 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 82 is 2-methylamino benzo thiazole-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 82 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 82 is 2-methylamino benzo thiazole-6-base rather than 3, and the 5-dichlorophenyl.
Table 83
The compound of table 83 is general formula (1) compounds, and wherein Ar is benzoxazole-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 83 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 83 is benzoxazole-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 83 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 83 is benzoxazole-6-base rather than 3, and the 5-dichlorophenyl.
Table 83A
The compound of table 83A is general formula (a 1) compound, and wherein Ar is benzo [b] thiophene-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 83A is identical with the compound 1 of table 1, except Ar in the compound 1 of table 83A is benzo [b] thiophene-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 83A, except Ar in the compound of table 83A is benzo [b] thiophene-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3
12 H Uncle-C 4H 9 Oil
Table 83B
The compound of table 83B is general formula (a 1) compound, and wherein Ar is cumarone-6-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of showing 83B is identical with the compound 1 of table 1, except Ar in the compound 1 of table 83B is cumarone-6-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 with table 1 is identical respectively for the compound 2-237 of table 83B, except Ar in the compound of table 83B is cumarone-6-base rather than 3, and the 5-dichlorophenyl.
Compound number R 2 R 3
12 H Uncle-C 4H 9 Oil
Table 84
The compound of table 84 is general formula (1) compounds, and wherein Ar is benzoxazole-6-base, and n is 0, and L is O, R 1Be ethyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 84 is identical with the compound 1 of table 84, except R in the compound 1 of table 84 1Be ethyl rather than methyl.Similarly, the compound 2-237 of the table 84 compound 2-237 with table 83 respectively is identical, except R in the compound of table 84 1Be ethyl rather than methyl.
Table 85
The compound of table 85 is general formula (1) compounds, and wherein Ar is 2,1-benzoisoxazole-5-base, and n is 0, L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 85 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 85 is 2, and 1-benzoisoxazole-5-base rather than 3,5-dichlorophenyl.Similarly, the compound 2-237 of the table 85 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 85 is 2, and 1-benzoisoxazole-5-base rather than 3,5-dichlorophenyl.
Table 86
The compound of table 86 is general formula (1) compounds, and wherein Ar is benzothiazole-5-base, and n is 0, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 86 is identical with the compound 1 of table 1, except Ar in the compound 1 of table 86 is benzothiazole-5-base rather than 3, and the 5-dichlorophenyl.Similarly, the compound 2-237 of the table 86 compound 2-237 with table 1 respectively is identical, except Ar in the compound of table 86 is benzothiazole-5-base rather than 3, and the 5-dichlorophenyl.
Table 87
The compound of table 87 is general formula (1) compounds, and wherein Ar is benzothiazole-5-base, and n is 0, and L is O, R 1Be ethyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 87 is identical with the compound 1 of table 87, except R in the compound 1 of table 87 1Be ethyl rather than methyl.Similarly, the compound 2-237 of the table 87 compound 2-237 with table 87 respectively is identical, except R in the compound of table 87 1Be ethyl rather than methyl.
Table 88-122
Table 88-122 just in time with table 1-35 corresponding (promptly table 88 is just in time corresponding with table 1, and table 89 is just in time corresponding with table 2, or the like), unique difference is that L is S rather than O in table 88-122.
Table 123-268
Table 123-268 just in time with table 1-122 corresponding (promptly table 123 is just in time corresponding with table 1, and table 124 is just in time corresponding with table 2, or the like), unique difference is that n is 1 rather than 0 in table 123-268.
Table 166
The compound of table 166 is general formula (1) compounds, and wherein Ar is cumarone-5-base, and n is 1, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 166 is identical with the compound 1 of table 1, and except Ar in the compound 1 of table 166 is cumarone-5-base rather than 3,5-dichlorophenyl and n are 1 rather than 0.Similarly, the compound 2-237 of the table 166 compound 2-237 with table 1 respectively is identical, and except Ar in the compound of table 166 is cumarone-5-base rather than 3,5-dichlorophenyl and n are 1 rather than 0.
Compound number R 2 R 3
12 H Uncle-C 4H 9 Oil
189 H C 6H 5-(CH 3) 2C- Oil
Table 269-414
Table 269-414 just in time with table 1-122 corresponding (promptly table 245 is just in time corresponding with table 1, and table 246 is just in time corresponding with table 2, or the like), unique difference is that n is 2 rather than 0 in table 269-414.
Table 312
The compound of table 312 is general formula (1) compounds, and wherein Ar is cumarone-5-base, and n is 2, and L is O, R 1Be methyl, R 2And R 3Has listed implication in the table 1.Therefore the compound 1 of table 312 is identical with the compound 1 of table 1, and except Ar in the compound 1 of table 312 is cumarone-5-base rather than 3,5-dichlorophenyl and n are 2 rather than 0.Similarly, the compound 2-237 of the table 312 compound 2-237 with table 1 respectively is identical, and except Ar in the compound of table 312 is cumarone-5-base rather than 3,5-dichlorophenyl and n are 2 rather than 0.
Compound number R 2 R 3
12 H Uncle-C 4H 9 140-143℃
189 H C 6H 5-(CH 3) 2C- 140-142℃
The compound of general formula (1) can be as preparation as described in the following scheme 1-4, Ar wherein, R 1, R 2And R 3Has the implication that above provides, R 5Be H or C 1-4Alkyl, R 10Be C 1-6Alkyl, optional substituted phenmethyl or optional substituted thienyl methyl, R 6, R 7, R 8, R 9, R 12And R 13Be H or C independently 1-3Alkyl, condition are to work as R 12And R 13When all being alkyl, its total number of carbon atoms is no more than 3, and m is 0,1 or 2, and DMF is N, and dinethylformamide, NBS are N-bromine succinimides, and NCS is that N-chloro-succinimide and MCPBA are m-chlorine peroxybenzoic acid.Other abbreviations definition in the text.
N be 0 and L be that formula (1) compound of O can prepare shown in scheme 1.The ester of formula (2), wherein R 5Be C 1-4Alkyl, can by with halogenating agent such as N-bromine succinimide, in The suitable solvent such as tetracol phenixin or acetonitrile, in the presence of radical initiator such as AIBN (azo-isopropyl cyanide) and light source, in room temperature reaction and by the halogen ester of halogenation production (3), wherein Hal is halogen atom such as bromine, chlorine and iodine to the reflux temperature of solvent.The compound of formula (3) is in the presence of alkali such as sodium hydride, in The suitable solvent such as DMF, with general formula R then 1The alkane thiol reaction of SH produces the compound of general formula (6), perhaps in The suitable solvent such as DMF, with alkane thiol salt R 1S -M +, wherein M is metal such as sodium or lithium, reaction produces the compound of general formula (6).
Scheme 1
Figure G05840077020070525D000551
As selection, the ester of general formula (4) can be in The suitable solvent such as tetracol phenixin or acetonitrile or methylene dichloride, 0 ℃ to the reflux temperature of solvent, with halide reagent such as N-chloro-succinimide or N-bromine succinimide or SULPHURYL CHLORIDE reaction by the halogen ester of halogenation production (5).The halogen ester of formula (5) and hydroxyl (mixing) aryl ArOH, wherein Ar defines as mentioned, in the presence of alkali such as potassium tert.-butoxide, salt of wormwood or sodium hydride, at the The suitable solvent such as the trimethyl carbinol, 1, among 4-dioxane or the DMF, in room temperature to the reflux temperature of solvent, reacting generating (6) compound.Formula (6) compound by with alkali metal hydroxide M +OH -In The suitable solvent such as aqueous methanol, ethanol or THF (tetrahydrofuran (THF)), to the reflux temperature of solvent, react, then carry out acidifying in room temperature, thus the acid of the production of being hydrolyzed (7).Use suitable activator such as HOBT (I-hydroxybenzotriazole) and EDC (1-ethyl-3-N, N-and methylamino propyl carbodiimide diimmonium salt hydrochlorate), 0 ℃ to the room temperature in The suitable solvent such as DMF, the amine condensation of the acid of formula (7) and formula (8), produce the compound of general formula (1), wherein n be 0 and L be O.
Shown in scheme 2, n is the compound of 1 or 2 general formula (1), is to be oxidized to sulfoxide (n is 1) or sulfone (n is 2) oxidation state prepares by the compound (1) with n=0.For example, the ester of general formula (6), wherein R 5Be C 1-4Alkyl, available oxidant such as sodium periodate in The suitable solvent such as ethanol under 0 ℃ of ester room temperature with the sulfoxide of its oxidation accepted way of doing sth (9).The sulfone of formula (10) can make by directly being reacted to the reflux temperature of solvent at 0 ℃ in The suitable solvent such as methylene dichloride by formula (6) compound and two equivalents or how normal oxygenant such as metachloroperbenzoic acid (MCPBA), is perhaps made by the sulfoxide of formula (9) and monovalent or the reaction of how normal metachloroperbenzoic acid.The sulfone of the sulfoxide of the sulfide of formula (6), formula (9) or formula (10) can be by reacting to the reflux temperature of solvent at 0 ℃ in The suitable solvent such as ethanol with alkali metal hydroxide, then carry out acidifying, thereby be hydrolyzed into corresponding acid (7), (11) or (12).Can use suitable activator such as HOBT and EDC, 0 ℃ to room temperature, make the acid of formula (7), (11) or (12) and the amine condensation of formula (8), produce the compound of general formula (1), wherein n is 0,1 or 2.
Similarly, n is 1 the formula (11) and the sulfoxide of formula (1), can use as mentioned above oxygenant such as sodium metaperiodate or-the chlorine peroxybenzoic acid is respectively by the sulfide preparation of formula (7) and formula (1).N is 2 the formula (12) and the sulfone of formula (1), can be as mentioned above by n be 0 formula (7) and formula (1) sulfide by use at least two normal oxygenants as-the chlorine peroxybenzoic acid makes, or be 1 the formula (11) and the sulfoxide of formula (1) by n, by use one or more normal oxygenants as-the chlorine peroxybenzoic acid makes.
The compound of formula (1) also can prepare shown in scheme 3.Use suitable activator such as HOBT and EDC, 0 ℃ to room temperature, make the acid of formula (13) and the amine condensation of formula (8), the compound of production (14).Use halogenating agent such as N-chloro-succinimide in The suitable solvent such as tetracol phenixin or acetonitrile, 0 ℃ to room temperature, make formula (14) compound by the compound of a halogenation accepted way of doing sth (16).The amine of formula (16) also can by the carboxylic acid halides of formula (15) by with the amine of formula (8), make in The suitable solvent such as methylene dichloride, reacting to the room temperature in the presence of alkali such as the triethylamine at 0 ℃.
Scheme 3
Figure G05840077020070525D000571
The halo sulfide of formula (16) can with hydroxyl (mixing) aryl ArOH, in the presence of alkali such as salt of wormwood or sodium hydride, in The suitable solvent such as DMF, 0 ℃ under 80 ℃, it is 0 formula (1) compound that reaction produces n.
Shown in scheme 4, the amine of general formula (18) or (20), described amine are R wherein 2Be the example of amine of the general formula (8) of H, can be respectively by using suitable alkali such as n-Butyl Lithium or sodium hydride, then and suitable alkylating reagent R 10LG such as alkyl iodide for example methyl-iodide react, and the amino alcohol alkylation of general formula (17) or (19) are formed the alkylated compound of general formula (18) or (20).Carbonyl derivative R 12COR 13(21), aldehyde for example, can with ammonia, the normally ammonia of ammonium chloride form, and prussiate, the aqueous solution form of sodium cyanide normally, reaction produces alpha-amino group alkynes (22) (Strecker is synthetic).
Scheme 4
Figure G05840077020070525D000581
Other amine of general formula (8) are commercially availablely maybe can make by normative document method or standard modifying method.
Thioamides (general formula (1) compound, wherein L=S (as derived from 2-(3-bromo-quinoline-6-base oxygen)-N-tertiary butyl-2-methyl sulfane base-thioacetamide of the compound 12 of table 72 13CNMR (CDCl3) δ (C=S) 193.3ppm}) can use sulfuration reagent such as thiophosphoric anhydride, Lawesson ' s or Davy ' s reagent to prepare by corresponding amide, or use normative document method or standard modifying method to make by corresponding thionic acid (thionoacids) or thion ester (thionoesters).
Hydroxyl (mixing) aryl ArOH be commercially available or can prepare by the normative document method (see, for example, Ann.Chem., Justus Liebigs (1966), 98-106 page or leaf, the synthetic 3-bromo-6-hydroxyl-quinoline that is used for preparation table 57 compound; Journal of the ChemicalSociety, Perkin Transactions 1:Organic and Bio-OrganicChemistry (1972-1999) (1982), (3), 815-21 page or leaf, synthetic benzo [b] thiophene-6-alcohol that is used for the compound of preparation table 83A; Journal of Medicinal Chemistry2004,47 (20), the 4829-4837 page or leaf, be used for the synthetic pure and mild European Journal of the cumarone-6-of Organic Chemistry (2000) that is used for preparation table 83B compound, (3), the 491-497 page or leaf, the synthetic 7-bromo-naphthalene-2-alcohol that is used for preparation table 67 compound).
Formula (1) compound is effective mycocide, can be used for preventing and treating one or more following cause of diseases: the mould Pyricularia oryzae of rice blast pears spore (Magnaporthe grisea) on rice and the wheat and other Puccinias on other hosts; Puccinia recondita Pucciniatriticina (or recondita) on the wheat, bar shaped handle rest fungus and other rest fungus, the barley handle rest fungus on the barley, bar shaped handle rest fungus and other rest fungus, with other hosts (turf for example, rye, coffee, pears, apple, peanut, sugar beet, vegetables and ornamental plant) on rest fungus; Two spore powdery mildews on the cucurbitaceous plant (for example melon); Barley, wheat, other powdery mildews on Blumeria on rye and the turf (or powdery mildew) standing grain powdery mildew (powdery mildew) and the various host, as the spot monofilament shell (Sphaerotheca macularis) on the hop, cucurbitaceous plant (the pale monofilament shell bacterium (Sphaerotheca fusca) (Sphaerotheca fuliginea) on the cucumber for example, Tartar's internal thread powdery mildew (Leveillula taurica) on tomato/eggplant and the green pepper, white cross hair list softgel shell (Podosphaera leucotricha) on the apple with grape vine on snag shell (Uncinula necator), cereal (wheat for example, barley, rye), cochliobolus on turf and other hosts belongs to (Cochliobolus spp.), Helminthosporium (Helminthosporiumspp.), nuclear cavity Pseudomonas (Drechslera spp.) (Pyrenophora spp.), Rhynchosporium spp (Rhynchosporium spp.), standing grain green-ball chamber bacterium (Mycosphaerellagraminicola) (wheat septoria (Septoria tritici)) and cereal leaf spoting bacteria (Phaeosphaeria nodorum) (many spores of clever withered shell (Stagonospora nodorum) or clever withered septoria musiva (Septoria nodorum)), rotten germ (Pseudocercosporellaherpotrichoides) of wheat-based and gaeumannomyce (Gaeumannomyces graminis); Peanut tail spore (Cercospora arachidicola) on the peanut and late pinta (Cercosporidiumpersona tum) and other hosts, sugar beet for example, banana, other Cercosporas on soybean and the rice; Tomato, strawberry, vegetables, the gray botrytis (Botrytis cinerea) (grey mold) on grape vine and other hosts and other Staphlosporonites on other hosts; Vegetables (for example Radix Dauci Sativae), rape, apple, tomato, potato, the Alternaria on cereal (for example wheat) and other hosts; Apple, pears, drupe, the Venturia (comprising venturia inaequalis (scab)) on woody nut and other hosts; Multiple host comprises the Cladosporium (Cladosporium spp.) on cereal (for example wheat) and the tomato; Drupe, the chain sclerotinia sclerotiorum on woody nut and other hosts belongs to (Monilinia spp.); Asia on tomato, turf, wheat, cucurbitaceous plant and other hosts belongs to (Didymella spp) every the spore shell; Rape, turf, rice, potato, the Phoma (Phoma spp.) on wheat and other hosts; Wheat, Aspergillus (Aspergillus spp.) and aureobasidium genus (Aureobasidium spp.) on timber and other hosts; Beans, wheat, the ascochyta (Ascochyta spp.) on barley and other hosts; Apple, pears, the mould genus of crawl handle (Stemphylium spp. (Pleospora spp.)) on onion and other hosts; Disease in summer on apple and the pears (bitter rot (enclosing small cluster shell) (Glomerella cingulata) for example, brown heart or grey speck of soybean (Botryosphaeria obtusa), fruit blotch (Mycosphaerella pomi), cedar apple rest fungus (the pure white glue rest fungus of Chinese juniper (Gymnosporangium juniperi-virginianae)), moorcoal disease (a kind of fruit, such as apple, pear, etc. glues shell spore (Gloeodes pomigena)), spot disease (Schizothyrium pomi) and white rot (grape seat chamber bacterium (Botryosphaeria dothidea))); It is mould that grape on the grape vine is given birth to single shaft; Other oidium, as the dish stalk of the lettuce on the lettuce mould (Bremia lactucae), soybean, tobacco, Peronospora on onion and other hosts, rule grass false downy mildew (Pseudoperonospora humuli) on the hop and the false downy mildew (Pseudoperonospora cubensis) of Cuba on the cucurbitaceous plant; Pythium (comprising ultimate corruption mould (Pythium ultimum)) on turf and other hosts; Phytophthora infestan on potato and the tomato (Phytophthora infestans) and vegetables, strawberry, avocado, pepper, ornamental plant, tobacco, other phytophthoras on cocoa and other hosts; Thanatephorus cucumeris(frank) donk on rice and the turf (Thanatephorus cucumeris) and various host such as wheat and barley, peanut, vegetables, other Rhizoctonias on cotton and the turf; Turf, peanut, potato, the Sclerotinia (Sclerotinia spp.) on rape and other hosts; Turf, the sclerotium (Sclerotium spp.) on peanut and other hosts; Gibberella fujikuroi on the rice (Gibberella fujikuroi); Comprise turf, the Colletotrichum (Colletotrichumspp.) on numerous hosts of coffee and vegetables; Rye grass subconjunctival capillaries disease (Laetisaria fuciformis) on the turf; Banana, peanut, oranges and tangerines, Semen Caryae Cathayensis, the mycosphaerella (Mycosphaerellaspp.) on pawpaw and other hosts; Oranges and tangerines, soybean, muskmelon, pears, on lupine and other hosts between the seat shell belong to (Diaporthe spp.); Oranges and tangerines, grape vine, olive, Semen Caryae Cathayensis, the Elsinoe (Elsinoe spp.) on rose and other hosts; Comprise hop, the Verticillium on numerous hosts of potato and tomato (Verticillium spp.); Bury Sclerotinia (Pyrenopeziza spp.) on rape and other hosts; Cause the Oncobasidium theobromae on the cocoa of tieing up pipe speckle top dry; Wheat various hosts but particularly, barley, fusarium on turf and the corn (Fusarium spp.), nuclear coral Pseudomonas (Typhula spp.), the mould patch of reaping hook (Microdochium nivale), Ustilago (Ustilago spp.), Urocystis (Urocystis spp.), Tilletia (Tilletia spp.) and ergot (Clavicepspurpurea); Sugar beet, the Ramularia (Ramulariaspp.) on barley and other hosts; (the Penicillium digitatum on the oranges and tangerines (Penicilliumdigitatum) for example of disease after the results of fruit particularly, Italy's mould (Penicillium italicum) and viride (Trichoderma viride), banana thorn dish spore (Colletotrichum musae) on the banana and the gray botrytis (Botrytis cinerea) on long spore of banana dish (Gloeosporium musarum) and the grape); Other germs on the grapevine, Eutypa lata particularly, grape Guignardia (Guignardia bidwellii), phelliuns igniarius (Phellinusigniarus), grape is given birth to Phomopsis (Phomopsis viticola), false cup fungi (Pseudopeziza tracheiphila) of microtubule fasolculus and hair Boreostereum vibrans (Stereum hirsutum); Other pathogenic agent on other germs on the trees (for example Lophodermium seditiosum) or the timber, Cephaloascus fragrans particularly, long beak shell belongs to (Ceratocystis spp.), Ophiostoma piceae, Penicillium, trichoderma pseudokiningii (Trichodermapseudokoningii), viride (Trichoderma viride), trichoderma harziarum (Trichoderma harzianum), aspergillus niger (Aspergillus niger), Leptographium lindbergi and aureobasidium pullulans (Aureobasidium pullulans); With the fungi vehicle of virus disease (for example as Gramineae on vectorial cereal of barley yellow mosaic virus (BYMV) how sticking mould and as the many slime moulds of beet (Polymyxa betae) on rhinoviral vectorial sugar beet).
Formula (1) compound is Xiang Ding, mobile to base or part within plant tissue, thereby effectively resists one or more fungies.In addition, formula (1) compound may be volatile, is enough to effectively resist under steam condition the fungi on one or more plants.
Therefore the invention provides the method for a kind of antagonism or control plant pathogenic fungi, comprise seed, plant or seed location to plant, plant or soil or any other plant growth medium for example nutritive medium use formula (1) compound of fungicidal significant quantity or contain formula (1) compound compositions.
Term used herein " plant " comprises seedling, shrub and trees.In addition, Fungicidal method of the present invention comprises protectiveness, therapeutic, interior absorption, the property rooted out and anti-sporulation processing.
Formula (1) compound preferably is used for agricultural, gardening and turfgrass with the form of composition.
For formula (1) compound being used for seed, plant or seed location or soil or any other growth medium of plant, plant, usually formula (1) compound is mixed with composition, wherein except that formula (1) compound, also comprises suitable inert diluent or carrier and optional tensio-active agent (SFA).SFA is a chemical preparations, can be by reducing the performance that interfacial tension changes interface (solid for example liquid/, liquid/gas or liquid/liquid interface), thus cause the change (for example dispersiveness, emulsifying property and wettability) of other performances.Preferred all compositions (solid and liquid preparation) contain 0.0001-95% by weight, more preferably 1-85%, for example formula of 5-60% (1) compound.Composition is generally used for preventing and treating fungi, therefore with 0.1g-10kg/ha, and preferred 1g-6kg/ha, more preferably the consumption of 1g-1kg/ha is used formula (1) compound.
When being used to dress seed, formula (1) compound is with every kilogram of seed 0.0001-10g (for example 0.001 or 0.05g), preferred 0.005-10g, and more preferably the consumption of 0.005-4g is used.
On the other hand, the invention provides a kind of fungicide composition, contain formula (1) compound of fungicidal significant quantity and carrier or the thinner that is suitable for.
On the other hand, the invention provides a kind of method of resisting and preventing and treating on-site fungi, comprise with formula (1) compound compositions that contains of fungicidal significant quantity and handle fungi or fungi location.
The optional majority kind of composition formulation, comprise pulvis (DP), soluble powder (SP), water-soluble granular formulation (SG), water-dispersible granules (WG), wettable powder (WP), granule (GR) (slowly-releasing or release soon), soluble concentrate (SL), finish (OL), ultra low volume liquids (UL), missible oil (EC), dispersible agent (DC), emulsion (oil-in-water (EW) and water-in-oil (EO)), microemulsion (ME), suspension agent (SC), aerosol, mist agent/fumicants, microcapsule suspending agent (CS) and seed treatment preparation.Under any circumstance the formulation of Xuan Zeing will depend on the specific purpose of expection and physics, chemistry and the biological property of formula (1) compound.
The preparation of pulvis (DP) can be by with formula (1) compound and one or more solid diluents (natural clay for example, kaolin, pyrophyllite, wilkinite, aluminum oxide, polynite, diatomite, chalk, diatomite, calcium phosphate, lime carbonate and magnesiumcarbonate, sulphur, lime, flour, talcum and other organic and inorganic solid support) and mixture mechanical mill become fine powder.
The preparation of soluble powder (SP) can be passed through formula (1) compound and one or more water-soluble inorganic salts (as sodium bicarbonate, yellow soda ash or sal epsom) or one or more water-soluble organic solid (as polysaccharide) and one or more optional wetting agents, and the mixture of one or more dispersion agents or described reagent mixes to improve water dispersible/solvability.Then mixture is ground to form fine powder.But same mixture also granulation forms water-soluble granular formulation (SG).
The preparation of wettable powder (WP) can be passed through formula (1) compound and one or more solid diluents or carrier, one or more wetting agents, mix to promote the dispersion in liquid with preferred one or more dispersion agents and one or more optional suspension agents.Then mixture is ground to form fine powder.But same composition also granulation forms water-dispersible granules (WG).
Granule (GR) can form by the mixture granulation with formula (1) compound and one or more atomizing solid diluents or carrier; or by preformed blank particle by formula (1) compound (or its solution in suitable reagent) is absorbed in the porous particulate material (as float stone; attapulgite; Fuller's earth; diatomite; diatomite or corn cob meal) in or by formula (1) compound (or its solution in suitable reagent) is adsorbed in the stone material (as sand; silicate; inorganic carbonate, vitriol or phosphoric acid salt) go up and dried if necessary formation.Be usually used in the auxiliary reagent that absorbs or adsorb and comprise solvent (as aliphatic series and aromatic petroleum solvent, alcohols, ethers, ketone and ester class) and tackiness agent (as polyvinylacetate, polyvinyl alcohol, dextrin, sugar and vegetables oil).Also can comprise one or more additives (for example emulsifying agent, wetting agent or dispersion agent) in the granule.
Dispersible agent (DC) can be by preparing formula (1) compound dissolution in water or organic solvent such as ketone, alcohol or glycol ether.These solution can contain tensio-active agent (for example be used for improving the water extent of dilution or prevent in the spray cistern crystallization).
Missible oil (EC) or oil-in-water emulsion (EW) can be by preparing formula (1) compound dissolution in organic solvent (the optional mixture that contains one or more thinners, one or more emulsifying agents or described reagent).The organic solvent that is applicable to missible oil comprises aromatic hydrocarbon, and (as alkylbenzene or alkylnaphthalene, for example SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a registered trademark), ketone (as pimelinketone or methylcyclohexanone), alcohols (as phenylcarbinol, furfuryl alcohol or butanols), N-alkyl pyrrolidone (as N-Methyl pyrrolidone or N-octylpyrrolidone), the dimethylformamide of lipid acid is (as C 8-C 10The lipid acid dimethylformamide) and hydrochloric ether.The EC product can spontaneous emulsification when adding water, produces the emulsion with abundant stability, can be by suitable device spray application.The preparation of EW comprises that the liquid of acquisition formula (1) compound is not (if it at room temperature is a liquid, then it may be usually less than 70 ℃ of fusings down in rational temperature) or solution (it is dissolved in the The suitable solvent), the emulsification in containing the water of one or more SFAs with gained liquid or solution under high shear then produces emulsion.The solvent that is applicable to EWs comprises vegetables oil, hydrochloric ether (as chlorobenzene), aromatic solvent (as alkylbenzene or alkylnaphthalene) and other suitable organic solvents of low solubility are arranged in water.
The preparation of microemulsion (ME) can be by mixing the thermodynamically stable isotropic liquid formulation of spontaneous generation with water with the mixture of one or more solvents and one or more SFA.Formula (1) compound is present in water or the solvent/SFA mixture at first.The solvent that is applicable to ME is included in those solvents that are used for EC or EW of describing in the context.ME can be oil-in-water or water-in-oil system (which kind of system exists by conductivity measurement is determined) and be applicable to mixing water dissolubility and oil-soluble pesticide in same preparation.ME is adapted at diluting in the water, keeps microemulsion or forms conventional O/w emulsion.
It is moisture or do not have an aqeous suspension that suspension agent (SC) can contain the finely divided insoluble solids particulate of formula (1) compound.SC can choose wantonly and use one or more dispersion agents by ball milling or pearl mill formula (1) solid chemical compound in suitable medium, produces the fine particle suspension of compound.One or more wetting agents can be comprised in the composition, and suspension agent can be contained to reduce particle sinking speed.As selection, formula (1) compound can be dry grinded and be added in the water that contains reagent mentioned above, produces the finished product of wishing.
Aerosol contains formula (1) compound and suitable propellent (for example normal butane).Formula (1) compound also can or be scattered in the suitable medium (for example water or water soluble liq such as n-propyl alcohol) by solvent, obtains being used for the composition of non-pressurized hand sprayer.
Formula (1) compound can mix with firework mixture under drying regime, forms to be applicable to the composition that produces the cigarette that contains described compound in enclosed space.
Microcapsule suspending agent (CS) can the mode similar to preparation EW preparation prepare, but other polymerization period is arranged, thereby obtains the water dispersion of oil droplet, and wherein each oil droplet is aggregated thing shell packing, and contains formula (1) compound and optional carrier or thinner.Polymer shell can produce by interfacial polycondensation reaction or agglomeration step.Composition can provide the slowly-releasing of formula (1) compound and can be used for seed treatment.Formula (1) compound also can be prepared in biodegradable polymeric matrices so that the slow controlled release of compound to be provided.
Composition can comprise one or more additives with the biological property that improves composition (for example wetting by improving, keep or in the distribution on surface; To handling the drag of the rainwater on the rear surface; Or the absorption of formula (1) compound or mobile).Described additive comprises tensio-active agent, oil base spray additives, for example mixture of some mineral oil or crude vegetal (as soya-bean oil and rapeseed oil) and these reagent and other biological reinforcing aids (composition of help or change formula (1) compound effects).
Formula (1) compound also can be processed as seed treatment agent, and for example dust composition comprises seed treatment dry powder doses (DS), the solvable pulvis of seed treatment (SS) but or seed treatment dispersion powder (WS), or liquid composition, comprise suspension agent (FS), liquor (LS) or microcapsule suspending agent (CS).DS, SS, WS, FS and LS preparation of compositions are closely similar with DP, SP, WP, SC and DC preparation of compositions mentioned above respectively.The good composition for treating of seed can comprise the auxiliary agent (for example mineral oil or anti-membrane-forming agent (film-forming barrier)) that is used for composition is adhered to seed.
Wetting agent, dispersion agent and emulsifying agent can be positively charged ion, negatively charged ion, both sexes or non-ionic type SFA.
Suitable cationic SFA comprises quaternary ammonium compound (for example cetyl trimethylammonium bromide), tetrahydroglyoxaline and amine salt.
Suitable negatively charged ion SFA comprises an alkali metal salt of lipid acid, the salt of vitriolic aliphatic mono (for example Sodium Lauryl Sulphate BP/USP), the salt of sulfonated aromatic compound (Sodium dodecylbenzene sulfonate for example, calcium dodecylbenzene sulphonate, butyl naphthalene sulfonate, and di-isopropyl-and the mixture of triisopropyl-sodium naphthalene sulfonate), ether sulfate, ether alcohol sulfate (for example bay ether-3-sodium sulfate), ether carboxylate (for example bay ether-3-carboxylic acid sodium), phosphate ester (reaction product of one or more Fatty Alcohol(C12-C14 and C12-C18) and phosphoric acid (mainly being monoesters) or and the reaction product (mainly being diester) of Vanadium Pentoxide in FLAKES, for example reaction product of lauryl alcohol and four phosphoric acid; Also have those in addition by the product of ethoxylation), sulphosuccinamate, paraffinic hydrocarbons or alkene sulfonate, taurate and sulfonated lignin.
Suitable both sexes SFA comprises trimethyl-glycine, propionic salt and glycinate.
Suitable ionic surfactant pack is drawn together alkylene oxide such as oxyethane, propylene oxide, butylene oxide ring or device mixture, with Fatty Alcohol(C12-C14 and C12-C18) (as oleyl alcohol or hexadecanol) or with the condensation product of alkylphenol (as octyl phenol, nonyl phenol or octyl cresol); The partial ester of derivation of self-long chain lipid acid or hexitan; The condensation product of described partial ester and oxyethane; Block polymer (comprising oxyethane and propylene oxide); Alkanolamide; Single ester (for example fatty acid polyglycol ester); Amine oxide (for example lauryl dimethyl amine oxide); And Yelkin TTS.
Suitable suspension agent comprises hydrophilic colloid (as polysaccharide, polyvinylpyrrolidone or Xylo-Mucine) and swelling clay (as wilkinite or attapulgite).
Formula (1) compound can be used by any known method of using Fungicidal compounds.For example, can directly formula (1) compound administration of preparing or not preparing be arrived any part of plant, comprise blade, stem, branch or root, seed before the plantation, or plant is growing other media that maybe will plant (as the soil around root, general soil, paddy field water either or hydroponic system), maybe it can be sprayed, dust, use, use, use or by composition (as the composition of particulate composition or water-soluble bag parcel) being distributed or mixing in soil or the aqueous environment and use as steam as cream or paste formulation by dipping.
Formula (1) compound also may be injected in the plant or uses electric atomizing technology or other lower volume methods to be sprayed on the plant, or uses by soil irrigation system or built on stilts (aerial) irrigation system.
The composition (aqueous solution or dispersion) that uses as aqueous compositions provides usually and contains the enriched material form of activeconstituents at high proportion, and this enriched material adds in the entry before use.These enriched materials, comprise DC, SC, EC, EW, ME, SG, SP, WP, WG and CS, usually need to stand standing storage and behind storage, can add to form aqueous compositions in the entry, and aqueous compositions will keep in the sufficiently long time evenly, so that can use by conventional spraying equipment.According to the purpose that expection is used, described aqueous compositions can contain formula (1) compound (for example 0.0001-10wt%) of variable.
Formula (1) compound can mix use with fertilizer (fertilizer of for example nitrogenous, potassium or phosphorus).Suitable preparation type comprises the fertiliser granulates agent.The suitable formula of 25wt% (1) compound at the most that contains of mixture.
Therefore, the present invention also provides a kind of Ru 2006101161, contains fertilizer and formula (1) compound.
Composition of the present invention can contain the compound of other biologically actives, for example micro-nutrients or have the compound of similar or complementary Fungicidally active, or the compound with plant growth regulating, weeding, desinsection, nematicide or acaricidal activity.
By comprising another kind of mycocide, comparable independent formula (1) compound of resulting composition has the more active or higher levels of intrinsic activity of wide spectrum.In addition, other mycocides may have synergism to the Fungicidally active of formula (1) compound.
Formula (1) compound can be unique activeconstituents of composition or can mix described other activeconstituents such as sterilant, mycocide, synergistic agent, weedicide or plant-growth regulator with one or more other activeconstituentss suitably the time.Other activeconstituents can: provide to have more broad spectrum of activity or more persistent composition in the location; The activity of collaborative enhancing or complementary (1) compound (for example by improving speed of action or overcoming resistance).Concrete other activeconstituents depends on the expected utility of composition.
The example that can be included in the Fungicidal compounds in the composition of the present invention is AC 382042 (N-(1-cyano group-1,2-dimethyl propyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide), Acibenzolar, alanycarb, aldimorph, anilazine, oxygen ring azoles, azafenidin, Azoxystrobin, M 9834, F-1991, the benzene metsulfovax, Bitertanol (biloxazol), bitertanol, blasticidin, niacinamide (newname of nicobifen), bromuconazole, bupirimate, Difolatan, Vancide 89, derosal, carbendazim chlorhydrate, carboxin, ring propionyl bacterium amine, Karvon, CGA 41396, CGA 41397, chinomethionate, chlorbenzthiazone, m-tetrachlorophthalodinitrile, chlorozolinate, clozylacon, copper-containing compound such as Cupravit, oxyquinazoline copper, copper sulfate, copper resinate, and Bordeaux mixture, cyamidazosulfamid, cyanogen frost azoles (IKF-916), cyflufenamid, white urea cyanogen, SN-108266, cyprodinil, debacarb, two-2-pyridyl disulfide 1,1 '-dioxide, dichlofluanid, straightforward; Two chlorine zarilamids, diclomezin, botran; The mould prestige of second, Difenoconazole, difenzoquat; The fluorine mepanipyrim, O, O-two-isopropyl-S-benzyl thiophosphate; Dimefluazole, dimetconazole, dimethirimol; Dimethomorph, ether bacterium amine, alkene azoles alcohol; The dinitro ester, dicyan anthraquinone, dodecyl alkyl dimethyl ammonium chloride; Dodemorph, dodine, doguadine; Edifenphos, fluorine ring azoles, Guardian; The phonetic phenol of second, (Z)-N-benzyl-N ([methyl (methyl-sulfo-ethyleneimino oxygen carbonyl) amino] sulphur)-Beta-alanine ethyl ester, Grandox fumigant; Oxazole bacterium ketone, Fenamidone, Fenarimol; RH-7592, fenfuram, fenhexamid; Zarilamid (AC 382042), fenpiclonil, fenpropidin; The butylbenzene morpholine, fentinacetate, fentin hydroxide; Fervam, ferimzone, fluorine pyridine amine; Cough up the bacterium nitrile, fluorine acyl bacterium amine, fluorine morpholine; Fluoroimide, fluorine Fluoxastrobin, fluorine quinoline azoles; Flusilazole, flusulfamide, fluorine acid amides; Flutriafol, folpet, fosetyl; Furidazol, furalaxyl, furan pyrrole bacterium amine; Guanoctine, own azoles alcohol, hydroxyisoxazole; Hymexazo (hymexazole) presses down mould azoles, glyoxalin; Iminoctadine, iminoctadine triacetate is planted the bacterium azoles; IBP, iprodione, isopropyl bacterium amine; The isopropyl butyl carbamate, Isoprothiolane, kasugarnycin; Kresoxim-methyl, LY186054, LY211795; LY 248908, Mancozeb, maneb; Mefenoxam, mepanipyrim, mebenil; Metalaxyl, Metalaxyl-M, metconazole; Carbatene, Carbatene-zinc, SSF 126; Metrafenone, MON65500 (N-pi-allyl-4,5-dimethyl-2-trimethyl silyl thiophene-3-formamide); Nitrile bacterium azoles, NTN0301, methylarsonic acid iron ammonium; Nickel dimethyldithiocarbamate, a nitre phthalein isopropyl ester, nuarimol; Ofurace; Organomercurial compound, the spirit of orysastrobin ， Evil frost; Oxasulfuron; Oxolinic acide ， Evil imidazoles, oxycarboxin; Pefurazoate; Penta bacterium azoles, Pencycuron, oxidation azophenlyene; Phosphoric acid; Rabcide, ZEN 90160, Polyoxin; Carbatene; Probenazole, Prochloraz, procymidone; Downy mildew becomes; The Propamocarb hydrochloride, propiconazole, Propineb; Propionic acid; Proquinazid, prothioconazoles, azoles bacterium amine ester; Ppyrazophos; Pyrifenox, phonetic mould amine, pyroquilon; Chlorine pyrrole furan ether; Pyrrolnitrin, quaternary ammonium compound, quinomethionate; Quinoxyfen; Pentachloronitrobenzene, silicon metsulfovax (MON 65500), S-presses down mould azoles; Simeconazoles; Sipconazole, sodium pentachlorophenol, volution bacterium amine; Streptomysin; Sulphur, Tebuconazole, tecloftalam; Tecnazene; Tetrafluoro ether azoles, probenazole, thiophene fluorine bacterium amine; 2-(thiocyanogen methyl mercapto) benzothiazole; Thiophanate-methyl, thiram, tiadinil; Timibenconazole; Tolelofos-methyl, Tolylfluanid, triazolone; Triadimenol; Butrizol, triazoxide, tricyclazole; Tridemorph; Oxime bacterium ester, fluorine bacterium azoles, triforine; Triticonazole; Valida, metham-sodium, ethene sclex; XRD-563; Dai Senxin, ziram, benzoyl bacterium amine and following formula: compound:.
Figure G05840077020070525D000681
Formula (1) compound can mix the invasion and attack that avoid kind of a biography, soil biography or leaf portion fungal disease with protective plant with soil, peat or other rooting medias.
Some mixtures can contain the activeconstituents with significantly different physics, chemistry or biological property, so it can not be applicable to simply with a kind of regular dosage form.In this case, can prepare other formulations.For example, when a kind of activeconstituents is water-insoluble solid, and another kind is when being water soluble liq, still can be by solid active agent being disperseed to become suspension (using and the similar preparation method of SC), but liquid actives is separated into emulsion (using the preparation method similar to EW) and every kind of activeconstituents all is scattered in same continuous aqueous phase.Resulting composition is suspended emulsion agent (SE).
The present invention describes by the following example, has wherein used following abbreviation:
Ml=milliliter m.p.=fusing point (uncorrected)
G=gram b.p.=boiling point
THF=tetrahydrofuran (THF) DMSO=methyl-sulphoxide
M +=ion massspectrum DMF=N, dinethylformamide
The unimodal d=of s=is bimodal
HOBT=1-hydroxybenzotriazole HOAT=7-azepine-I-hydroxybenzotriazole
The wide single cutting edge of a knife or a sword NMR=nucleus magnetic resonance of bs=
T=triplet HPLC=high performance liquid chromatography
Q=quartet TLC=thin-layer chromatography
M=multiplet glc=gas-liquid chromatograph
Ppm=1,000,000/EDC=1-ethyl-3-N, the N-dimethylamino
M=mole base propyl carbodiimide diimmonium salt hydrochlorate
Embodiment 1
This embodiment has illustrated the preparation of 2-(3, the 5-dichlorophenoxy)-2-methylthio group-N-2-methyl-prop-2-yl acetamide (compound 12 of table 1)
Stage 1: preparation 2-methylthio group-2-(3, the 5-dichlorophenoxy) acetate
Step 1
2-bromo-2-(3, the 5-dichlorophenoxy) tert.-butyl acetate (1.0g) is dissolved in 1, in the 4-dioxane (3ml), in mixture, adds sulfo-sodium methylate (0.218g).The light yellow suspension that obtains was at room temperature stirred 5 hours, stored then 18 hours.Evaporating solvent adds water, with ethyl acetate (100ml) extracting twice water layer.Organic layer is merged, use the salt water washing, dried over mgso is filtered and is evaporated, and obtains 2-methylthio group-2-(3, the 5-dichlorophenoxy) tert.-butyl acetate, is light yellow solid (0.80g), need not to be further purified to be used for next step.
1H NMR(CDCl 3)δppm：1.52(9H，s)；2.19(3H，s)，5.39(1H，s)；6.92(2H，d)；7.04(1H，t)。
Step 2
At room temperature, step 1 product (0.2g) in methyl alcohol (3ml) adds water (1ml) solution of sodium hydroxide (0.050g).Reaction is stirred and was carried out 2 hours, and evaporating solvent adds entry and ethyl acetate then.Water phase separated is used the diluted hydrochloric acid aqueous solution acidifying, uses ethyl acetate extraction then.Merge organic phase, dried over mgso is filtered and evaporation, obtains 2-methylthio group-2-(3, the 5-dichlorophenoxy) acetate, is light yellow gluey thing (0.153g).
1H NMR(CDCl 3)δppm：2.21(3H，s)；5.59(1H，s)；6.95(2H，s)；7.08(1H，s)。
Stage 2
Will be at anhydrous N, 2-methylthio group-2-in the dinethylformamide (6ml) (3, the 5-dichlorophenoxy) acetate (0.27g) was at room temperature used tert-butylamine (0.077g), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.211g), HOAt (0.15g) and triethylamine (0.28ml) stir process 10 hours.Mixture is poured in the water,, merged extract,, use dried over mgso then, filter and reduction vaporization, obtain oily matter with saturated aqueous sodium carbonate, water washing (three times) with ethyl acetate extraction (three times).Oily matter is by chromatographic separation (silicon-dioxide; Hexane/ethyl acetate, 95: 5 volume ratios), obtain the product that needs, 0.03g is light yellow solid, m.p.125-126 ℃.
1H NMR(CDCl 3)δppm：1.36(9H，s)；2.08(3H，s)；5.34(1H，s)；6.24(1H，bs)；6.86(2H，d)；9.02(1H，t)。
Following acid amides uses the similarity method preparation.
The compound 122 of table 1: use 2-amino methyl furans, 1H NMR (CDCl 3) δ ppm:2.10 (3H, s); 4.48-4.66 (2H, 2xdd); 5.56 (1H, s); 6.29 (1H, d); 6.33 (1H, m); 6.88 (1H, bs); 6.92 (2H, d); 7.09 (1H, t); 7.38 (1H, m).
The compound 150 of table 1: use phenmethyl amine, 1H NMR (CDCl 3) δ ppm:2.13 (3H, s); 4.48-4.64 (2H, 4xd); 5.57 (1H, s); 6.86 (1H, s); 6.92 (1H, s); 7.08 (1H, t); 7.30-7.38 (5H, m).
Embodiment 2
This embodiment has illustrated 2-(3,4,5-trimethylammonium phenoxy group)-preparation of 2-methylthio group-N-(2-methyl-third-2-yl) ethanamide (compound 12 of table 13) and 2-(4-bromo-3,5-dimethyl phenoxy)-2-methylthio group-N-(2-methyl-third-2-yl) ethanamide (compound 12 of table 15)
The preparation of stage 1:2-methylthio group-2-(3,4,5-trimethylammonium phenoxy group) acetate
The preparation of step 1:2-chloro-2-methylmercaptan ethyl acetoacetic ester
At 0 ℃, to 2-methylmercaptan ethyl acetoacetic ester (10.0g) in the stirred solution of anhydrous acetonitrile (50ml) the portion-wise addition N-chloro-succinimide (NCS 9.8g), keeps temperature of reaction to be lower than 5 ℃ during the interpolation.Mixture was stirred 0.5 hour, and then add NCS (0.5g) to finish reaction, suspension restir 0.5 hour.Use the saturated sodium bicarbonate aqueous solution treating mixture, separate organic phase, water extracted with diethyl ether (twice).Merge organic moiety, with sodium bicarbonate aqueous solution washing (twice), dried over mgso is used in salt water washing (twice) then, filters and solvent evaporated under reduced pressure, obtains 2-chloro-2-methylmercaptan ethyl acetoacetic ester, (9.2g), is colourless liquid.Product is used for next stage, need not to be further purified.
1H NMR(CDCl 3)δppm：1.32-1.36(3H，t)；2.32(3H，s)；4.26-4.32(2H，q)；5.36(1H，s)。
The preparation of step 2:2-methylthio group-2-(3,4,5-trimethylammonium phenoxy group) ethyl acetate
Under nitrogen atmosphere, at room temperature, in 5 minutes to sodium hydride (0.33g, 60% in mineral oil) at anhydrous N, add 3,4 in the stirred suspension of dinethylformamide (2ml), the N of 5-pseudocuminol (1.0g), dinethylformamide (20ml) solution.Mixture was stirred 1 hour, use N, dinethylformamide (40ml) dilution, drip 2-chloro-2-ethyl thioacetate (1.87g) then simultaneously at N, solution in the dinethylformamide (10ml) and be heated to 50 ℃ Anhydrous potassium carbonate (1.5g) at the stirred suspension of dry DMF (10ml) stirred 0.75 hour.Mixture is cooled to room temperature, pours in the water, use ethyl acetate extraction (three times) then.Merge extract, wash (three times) with water, dried over mgso, evaporation obtains the 2.15g yellow oil then, wherein contains 2-methylthio group-2-(3,4,5-trimethylammonium phenoxy group) ethyl acetate and some unreacted pseudocuminols.Part oil is by chromatographic separation (silicon-dioxide; Hexane: ethyl acetate), obtain 2-methylthio group-2-(3,4,5-trimethylammonium phenoxy group) ethyl acetate light yellow oil pure sample originally.Remaining oil is used for step 3, need not to be further purified.
1H NMR(CDCl 3)δppm：1.30-1.34(3H，t)；2.10(3H，s)；2.20(3H，s)；2.26(6H，s)；4.28-4.36(2H，m)；5.56(1H，s)；6.70(2H，s)。
Step 3
The product of step 2 (2.0g) was stirred 2 hours down at 60 ℃ at THF (10ml) and the solution that contains in the water (3ml) of sodium hydroxide (0.4g), be cooled to room temperature then, reduction vaporization, dilute with water also washs with ether.Contain water section dilute hydrochloric acid acidifying, with ethyl acetate extraction (three times).Merge extract, use the salt water washing, dried over mgso, evaporation obtains 2-methylthio group-2-(3,4,5-trimethylammonium phenoxy group) acetate then, and 1.05g is yellow jelly.Part jelly is by chromatographic separation (silicon-dioxide; Ethyl acetate, methyl alcohol then) produce analyzing samples, remaining being used for need not to be further purified next stage.
1H NMR(CDCl 3)δppm：2.12(3H，s)；2.24(3H，s)；2.26(6H，s)；5.64(1H，s)；6.72(2H，s)。
Stage 2
With the method in stage 2 of being similar to embodiment 1,, produce 2-methylthio group-2-(3,4,5-trimethylammonium phenoxy group)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide with 2-methylthio group-2-(3,4,5-trimethylammonium phenoxy group) acetate and tert-butylamine condensation.
1H NMR(CDCl 3)δppm：1.34(9H，s)；2.04(3H，s)；2.08(3H，s)；2.20(6H，s)；5.34(1H，s)；6.44(1H，s)；6.60(2H，s)。
With the method for the step 1 in stage 1 of being similar to embodiment 2, with 4-bromo-3,5-xylenol and 2-bromo-2-methylthio group acetic acid ethyl reaction produce 2-methylthio group-2-(4-bromo-3,5-dimethyl phenoxy) ethyl acetate, are light yellow liquid.
1H NMR(CDCl 3)δppm：1.33(3H，t)；2.20(3H，s)；2.39(6H，s)；4.31(2H，m)；5.53(1H，s)；6.77(2H，s)。
With the method for the step 1 in stage 1 of being similar to embodiment 2, with 4-cyano group-3,5-xylenol and 2-chloro-2-methylthio group acetic acid ethyl reaction produce 2-methylthio group-2-(4-cyano group-3,5-dimethyl phenoxy) ethyl acetate, are light yellow liquid.
1H NMR(CDCl 3)δppm：1.34(3H，t)；2.20(3H，s)；2.51(6H，s)；4.32(2H，q)；5.49(1H，s)；6.75(2H，s)。
Method with the step 2 in stage 1 of being similar to embodiment 1 with 2-methylthio group-2-(4-bromo-3,5-dimethyl phenoxy) hydrolysis of ethyl acetate, produces 2-methylthio group-2-(4-bromo-3,5-dimethyl phenoxy) acetate, is pale solid.
1H NMR(CDCl 3)δppm：2.23(3H，s)；2.40(6H，s)；5.61(1H，s)；6.79(2H，s)。
Method with the step 2 in stage 1 of being similar to embodiment 1 with 2-methylthio group-2-(4-cyano group-3,5-dimethyl phenoxy) hydrolysis of ethyl acetate, produces 2-methylthio group-2-(4-cyano group-3,5-dimethyl phenoxy) acetate, is colorless solid.
1H NMR(CDCl 3)δppm：2.24(3H，s)；2.52(6H，s)；5.67(1H，s)；6.78(2H，s)。
With the method in stage 2 of being similar to embodiment 1, with 2-methylthio group-2 (4-bromo-3,5-dimethyl phenoxy) acetate and tert-butylamine condensation, produce 2-(4-bromo-3, the 5-dimethyl phenoxy)-and 2-methylthio group-N-(2-methyl-third-2-yl) ethanamide, be colorless solid, m.p.123-125 ℃.
1H NMR(CDCl 3)δppm：1.41(9H，s)；2.14(3H，s)；2.39(6H，s)；5.39(1H，s)；6.41(1H，s)；6.74(2H，s)。
Following acid amides uses the similarity method preparation.
The compound 52 of table 13: use 2-cyano group-1-methoxyl group-third-2-base amine, 1HNMR (CH 3CN) δ ppm:3.40 (3H, 2xs); 3.66 (2H, m); 5.58 (1H, 2xs); 6.68 (2H, s); 7.25 (1H, 2xs).
The compound 120 of table 13: use thiazol-2-yl amine, 1H NMR (CH 3CN) δ ppm:5.85 (1H, s); 6.76 (2H, s); 7.10 (1H, d); 7.45 (1H, d).
The compound 70 of table 13: use allyl amine, 1H NMR (CH 3CN) δ ppm:3.83 (2H, t); 5.10 (2H, m); 5.55 (1H, s); 5.82 (1H, m); 6.68 (2H, s); 7.23 (1H, s).
The compound 150 of table 13: use phenmethyl amine, 1H NMR (CH 3CN) δ ppm:5.57 (1H, s); 6.67 (2H, s); 7.26 (5H, m); 7.58 (1H, s).
The compound 124 of table 13: use thienyl methyl amine, 1H NMR (CH 3CN) δ ppm:4.56 (2H, t); 5.54 (1H, s); 6.66 (2H, s); 6.92 (2H, m); 7.24 (1H, d); 7.64 (1H, s).
The compound 47 of table 17: use 1-methoxyl group-2-methyl-prop-2-base amine and 2-methylthio group-2-(4-cyano group-3,5-dimethyl phenoxy) acetate, 1H NMR (CDCl 3) δ ppm:1.36 (3H, s); 1.40 (3H, s); 2.15 (3H, s); 2.51 (6H, s); 3.38 (3H, s); 3.39 (2H, q); 5.49 (1H, s); 6.63 (1H, s); 6.73 (2H, s), colorless solid m.p.123-125 ℃.
Embodiment 3
Present embodiment has illustrated the preparation of 2-(5-chloropyridine base-3-oxygen)-2-(methylthio group)-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 70)
The preparation of stage 1:2-bromo-2-methylmercaptan ethyl acetoacetic ester
At 15 ℃, to 2-methylmercaptan ethyl acetoacetic ester (40.2g) in the stirred solution of tetracol phenixin (250ml) portion-wise addition N-bromine succinimide (NBS 54g), keeps temperature of reaction to be lower than 20 ℃ during the interpolation.Mixture was stirred 5 hours, and then add in batches NBS (10g) and, reacted restir 18 hours.Mixture is the salt water washing with yellow soda ash then, and dried over mgso is filtered and solvent evaporated under reduced pressure, produces (56g) orange liquid, wherein contains 10% unreacted 2-methylmercaptan ethyl acetoacetic ester.Product is used for next stage, need not to be further purified.Obtain the analyzing samples of 2-bromo-2-methylmercaptan ethyl acetoacetic ester by vacuum distilling, when 0.1mm Hg b.p.54-56 ℃.
1H NMR(CDCl 3)δppm：1.30(3H，s)；2.34(3H，s)；4.26(2H，q)；5.39(1H，s)。
Stage 2:2-(5-chloropyridine base-3-oxygen)-2-(methylthio group)-N-(2-methyl-prop-2-yl) second The preparation of acid amides
Step 1
5-chloro-3-pyridone (1.30g), 2-bromo-2-methylmercaptan ethyl acetoacetic ester (2.43g, 70% is pure) and Anhydrous potassium carbonate (1.38g) are stirred in dried DMF (15ml) and be heated to 80 ℃, stirred 1 hour.Mixture is cooled to room temperature, pours in the water, use extracted with diethyl ether (three times) then.Merge extract, wash with water and dried over mgso, then evaporation, produce oil, by purification by flash chromatography on silica gel (40-60 order), with hexane/ethyl acetate (1: 1 volume ratio) wash-out, produce 2-(5-chloropyridine base-3-oxygen)-2-(methylthio group) ethyl acetate, be orange oil (0.65g).
1H NMR(CDCl 3)δppm：1.34-1.38(3H，t)；2.20(3H，s)；4.30-4.38(2H，m)；5.58(1H，s)；7.38(1H，m)；8.30-8.32(2H，d)。
Step 2
The product (0.62g) of step 1 was stirred 1.5 hours down at 60 ℃ at THF (10ml) and the solution that contains in the water (3ml) of sodium hydroxide (0.19g), be cooled to room temperature then, and stored 18 hours.With the mixture evaporation, residue diluted with water is washed with ether then.Contain water section dilute hydrochloric acid acidifying, use ethyl acetate extraction.Merge extract, wash with water, dried over mgso, evaporation then produces 2-(5-chloropyridine base-3-oxygen)-2-(methylthio group) acetate, and 0.48g is the deep yellow jelly.
1H NMR(CDCl 3)δppm：2.24(3H，s)；5.72(1H，s)；7.54(1H，m)；8.34(1H，s)；8.40(1H，s)；9.52(1H，bs)。
Step 3
With with stages 2 similar methods of embodiment 1, with 2-(5-chloropyridine base-3-oxygen)-2-(methylthio group) acetate and tert-butylamine condensation, produce the product that needs, be water white oil.
1H NMR(CDCl 3)δppm：1.41(9H，s)；2.14(3H，s)；5.47(1H，s)；6.35(1H，bs)；7.36(1H，t)；8.28(1H，d)；8.30(1H，d)。
Following acid amides uses the similarity method preparation:
The compound 50 of table 70: use 1-methylthio group-2-methyl-prop-2-base amine, light yellow oil, 1HNMR (CDCl 3) δ ppm:1.48 (6H, s); 2.17 (3H, s); 2.19 (3H, s); 2.97 (2H, dd); 5.47 (1H, s); 6.63 (1H, s); 7.39 (1H, t); 8.30 (1H, d); 8.32 (1H, d).
The compound 52 of table 70: use 2-cyano group-1-methoxy propyl-2-base amine, jelly, 1HNMR (CDCl 3) δ ppm:1.81 (3H, 2xs); 2.18 (3H, 2xs); 3.52 (3H, 2xs); 2.64-3.80 (2H, 4xd); 5.59 ﹠amp; 5.60 (1H, 2xs); 7.02 ﹠amp; 7.07 (1H, 2xs); 7.39 (1H, m); 8.31 (1H, m); 8.35 (1H, m), data are consistent with 1: 1 non-corresponding isomer mixture.
Embodiment 4
Present embodiment has illustrated the preparation of 2-(benzothiazolyl-6-oxygen)-2-(methylthio group)-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 78)
The preparation of stage 1:6-hydroxybenzothiazole
The preparation of step 1:6-methoxyl group benzo thiazole
At 65 ℃, in 35 minutes, will be added drop-wise in the stirred solution of nitrite tert-butyl (9.9ml) in DMF (40ml) in the 2-amino-solution of 6-methoxyl group benzo thiazole (9.0g) in dry DMF (10ml).Temperature＜73 ℃ that keep mixture in the interpolation process.Benzothiazole solution add finish after, with dark red solution restir 15 minutes, be cooled to room temperature, pour into then in the dilute hydrochloric acid (200ml) and and dilute with salt solution.Garnet suspension extracted with diethyl ether, solid filtering, and then water and ether washing.Merge ethereal extract, contain water section and use ethyl acetate extraction again.Merge organic moiety, wash with water, dried over mgso, evaporation then produces brown solid.Solid with ethane/ethyl acetate (4: 1 volume ratios) wash-out, produces 6-methoxyl group benzo thiazole by flash column chromatography (40-60 order) purifying on silica gel, is colorless solid (2.1g).
1H NMR(CDCl 3)δppm：3.89(3H，s)；7.12(1H，dd)；7.40(1H，d)；8.01(1H，d)；8.82(1H，s)。
Step 2:
The solution of product (1.2g) in Hydrogen bromide (10ml, 48%) of step 1 120 ℃ of stirring heating 6 hours, was at room temperature stored 2 days then.The pale yellow solution of heat produces suspension when cooling.Make the suspension dissolving by adding water, by adding the pH regulator to 6 of sodium bicarbonate with solution, the solid that is settled out leaches from solution, washes with water and be pumped to dried then.Solid is dissolved in ethyl acetate, and solution produces the 6-hydroxybenzothiazole with dried over mgso and evaporation, is colorless solid (1.05g).
1H NMR(CDCl 3)δppm：7.07(1H，dd)；7.91(1H，d)；8.76(1H，d)；9.18(1H，s)。
The preparation of stage 2:2-(benzothiazolyl-6-oxygen)-2-methylthio group acetate
The preparation of step 1:2-(benzothiazolyl-6-oxygen)-2-(methylthio group) acetic ester
Under 80 ℃, 6-hydroxybenzothiazole (1.10g), 2-bromo-2-methylmercaptan ethyl acetoacetic ester (2.22g, 73% is pure) and Anhydrous potassium carbonate (2.0g) were stirred 0.5 hour in dry DMF (5ml), be cooled to room temperature then.Mixture is poured in the saturated aqueous ammonium chloride, used the dilute hydrochloric acid acidifying, use extracted with diethyl ether then.Extract washes with water, dried over mgso, and evaporation produces brown jelly.Jelly with hexane/ethyl acetate (1: 1 volume ratio) wash-out, produces 2-(benzothiazolyl-6-oxygen)-2-(methylthio group) ethyl acetate by the flash column chromatography purifying (40-60 order) on silica gel, is yellow solid (0.50g).
1H NMR(CDCl 3)δppm：1.37(3H，t)；2.27(3H，s)；4.30-4.42(2H，m)；5.65(1H，s)；7.28(1H，m)；7.59(1H，m)；8.08(1H，d)；8.90(1H，s)。
The preparation of step 2:2-(benzothiazolyl-6-oxygen)-2-(methylthio group) acetate
At room temperature, in the stirred solution of THF (4ml), add the solution of lithium hydroxide monohydrate (0.076g) in water (1ml) to 2-(benzothiazolyl-6-oxygen)-2-(methylthio group) ethyl acetate (0.50g).After 1 hour, extracted with diethyl ether is used in mixture dilute sulphuric acid acidifying, the extract dried over mgso, and evaporation then produces 2-(benzothiazolyl-6-oxygen)-2-(methylthio group) acetate, is light yellow solid (0.45g).
1H NMR(CDCl 3)δppm：2.28(3H，s)；5.72(1H，s)；7.28(1H，dd)；7.60(1H，m)；8.11(1H，d)；8.99(1H，s)。
Step 3
With with stages 2 similar methods of embodiment 1, with 2-(benzothiazolyl-6-oxygen)-2-(methylthio group) acetate and tert-butylamine condensation, produce 2-(benzothiazolyl-6-oxygen)-2-(methylthio group)-N-2-methyl-prop-2-yl acetamide.
1H NMR(CH 3CN)δppm：1.34(9H，s)；5.56(1H，s)；6.69(1H，s)；7.25(1H，d)；7.66(1H，s)；7.98(1H，d)；8.96(1H，s)。
Following acid amides uses the similarity method preparation.
The compound 70 of table 78: use allyl amine, 1H NMR (CH 3CN) δ ppm:3.86 (2H, m); 5.56 (1H, s); 5.84 (1H, m); 7.26 (1H, d); 7.36 (1H, m); 7.36 (2H, d); 7.68 (1H, s); 7.99 (1H, d); 8.97 (1H, s).
The compound 189 of table 78: use 2-phenyl-third-2-base amine, 1H NMR (CH 3CN) δ ppm:1.60 (6H, s); 5.61 (1H, s); 7.17 (1H, t); 7.25 (5H, m); 7.36 (2H, d); 7.66 (1H, s); 8.00 (1H, d); 8.98 (1H, s).
The compound 35 of table 78: use 2-cyano group-third-2-base amine, 1H NMR (CH 3CN) δ ppm:1.68 (6H, d); 5.71 (1H, s); 7.30 (1H, m); 7.34 (1H, s); 7.69 (1H, s); 7.99 (1H, d); 8.98 (1H, s).
The compound 133 of table 78: use the 4-fluoroaniline, 1H NMR (CDCl 3) δ ppm:2.24 (3H, s); 5.74 (1H, s); 7.08 (2H, t); 7.28 (1H, m); 7.61 (3H, m); 8.10 (1H, d); 8.40 (1H, s); 8.94 (1H, s).
The compound 52 of table 78: use 2-cyano group-1-methoxyl group-third-2-base amine, 1HNMR (CDCl 3) δ ppm:1.81 (3H, 2xs); 2.20 (3H, s); 3.52 (3H, 2xs); 3.68 (1H, m); 3.78 (1H, m); 5.63 (1H, 2xs); 7.15 (1H, 2xs); 7.24 (1H, m); 7.60 (1H, m); 8.10 (1H, d); 8.94 (1H, s).
Embodiment 5
Present embodiment has illustrated the preparation of 2-(3-chloroquinoline base-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 58)
The preparation of stage 1:3-chloro-6-hydroxyquinoline
In the stirred solution of N-methylpyrrolidin-2-ketone (12ml, thereby make nitrogen bubble pass through the solution deoxidation), add cupric chloride (1) (1.10g) and Repone K (1.66g) to 3-bromo-6-hydroxyquinoline (1.0g).Under nitrogen atmosphere with mixture heating up to 120 ℃ 2 hours, then 170 ℃ 2 hours.Reaction mixture dilutes with saturated aqueous ammonium chloride, adds ethyl acetate, the product that stirs the mixture and need with dissolving.Mixture is filtered to remove insoluble material, separate organic phase.Water ethyl acetate extraction (three times), insoluble material washs with hot ethyl acetate.The combined ethyl acetate part washes with water, dried over mgso, and reduction vaporization produces solid then.This solid is passed through chromatogram (silicon-dioxide; 9: 1 volume ratios of ethyl acetate/hexane) separate, produce 3-chloro-6-hydroxyquinoline, 0.7g is colorless solid.
1H NMR(CDCl 3)δppm：7.06(1H，d)；7.35(1H，dd)；7.91(1H，d)；7.96(1H，d)；8.59(1H，d)；9.55(1H，s)。
Stage 2
Step 1
At room temperature, in 5 minutes, in containing stirred solution among the dried DMF (200ml) of Anhydrous potassium carbonate (20.7g), 3-chloro-6-hydroxyquinoline (8.98g) drips 2-bromo-2-methylmercaptan ethyl acetoacetic ester (13.0g) at N, the solution in the dinethylformamide (50ml).Mixture is cooled to room temperature then 70-75 ℃ of heating 2.5 hours, and dilute with water is also used ethyl acetate extraction (four times).Merge extract, use the salt water washing, dried over mgso is filtered and reduction vaporization, produces the brown oil (21g) of the product that contains needs, can be used for next stage, need not to be further purified.Part oil (0.5g) is by chromatographic separation (silicon-dioxide; Hexane: ethyl acetate), produce 0.18g 2 (3-chloro-6-oxygen quinoline)-2-methylmercaptan ethyl acetoacetic ester, be yellow oil.
1H NMR(CDCl 3)δppm：1.34-1.38(3H，t)；2.26(3H，s)；4.30-4.38(2H，m)；5.72(1H，s)7.16(1H，d)；7.48-7.52(1H，dd)；8.02-8.06(2H，m)；8.72(1H，s)。
Step 2
At room temperature, in the stirred solution of product (20.5g) in tetrahydrofuran (THF) (150ml) of stages 2 step 1, add water (15ml) solution of sodium hydroxide (3.3g).Mixture was stirred 3 hours reduction vaporization then, residue diluted with water and with ether washing (twice).Contain water section concentrated hydrochloric acid acidifying, produce brown precipitate, it is leached from solution, with cold water washing and absorb water to driedly, produce 2 (3-chloroquinoline base-6-oxygen)-2-methylthio group acetate (8.5g), m.p.173-174 ℃.
1H NMR(DMSO-d6)δppm：2.16(3H，s)；6.10(1H，s)7.50(1H，m)；7.54-7.58(1H，dd)；7.98-8.02(1H，d)；8.44(1H，s)；8.76(1H，s)；13.6(1H，bs)。
Step 3
With with stages 2 similar methods of embodiment 1, with 2-(3-chloroquinoline base-6-oxygen)-2-methylthio group acetate and tert-butylamine condensation, produce the product that needs.
1H NMR(CH 3CN)δppm：5.64(1H，s)；6.71(1H，s)；7.30(1H，s)；7.51(1H，d)；7.98(1H，d)；8.16(1H，s)；8.68(1H，s)。
Following acid amides uses the similarity method preparation.
The compound 35 of table 58: use 2-cyano group-third-2-base amine, 1H NMR (CH 3CN) δ ppm:5.80 (1H, s); 7.32 (1H, s); 7.36 (1H, s); 7.52 (1H, d); 7.99 (1H, d); 8.18 (1H, s); 8.68 (1H, s).
The compound 128 of table 58: use the 2-cyano-aniline, 1H NMR (CH 3CN) δ ppm:6.03 (1H, s); 7.35 (1H, t); 7.46 (1H, s); 7.59 (1H, d); 7.68 (1H, t); 7.74 (1H, d); 7.88 (1H, d); 8.04 (1H, d); 8.23 (1H, s); 8.71 (1H, s); 9.18 (1H, s).
The compound 150 of table 58: use phenmethyl amine, 1H NMR (CH 3CN) δ ppm:4.42 (2H, m); 5.81 (1H, s); 7.26 (6H, m); 7.50 (1H, d); 7.71 (1H, s); 7.98 (1H, d); 8.16 (1H, s); 8.68 (1H, s).
The compound 70 of table 58: use allyl amine, 1H NMR (CH 3CN) δ ppm:3.86 (2H, m); 5.06 (1H, d); 5.14 (1H, d); 5.80 (1H, s); 5.86 (1H, m); 7.32 (1H, s); 7.36 (1H, s); 7.52 (1H, d); 7.99 (1H, d); 8.18 (1H, s); 8.68 (1H, s).
The compound 120 of table 58: use thiazol-2-yl amine, 1H NMR (CH 3CN) δ ppm:6.10 (1H, s); 7.14 (1H, d); 7.42 (1H, d); 7.48 (1H, d); 7.62 (1H, d); 8.04 (1H, d); 8.23 (1H, s); 8.72 (1H, s).
The compound 122 of table 58: use furfuryl group amine, 1H NMR (CH 3CN) δ ppm:4.40 (2H, m); 5.78 (1H, s); 6.21 (1H, s); 6.31 (1H, s); 7.30 (1H, s); 7.36 (1H, s); 7.50 (1H, d); 7.62 (1H, s); 7.98 (1H, d); 8.16 (1H, s); 8.68 (1H, s).
The compound 124 of table 58: use thienyl methyl amine, 1H NMR (CH 3CN) δ ppm:4.58 (2H, m); 5.78 (1H, s); 6.90 (1H, s); 6.95 (1H, s); 7.12 (1H, d); 7.30 (1H, s); 7.50 (1H, d); 7.78 (1H, s); 7.96 (1H, s); 8.14 (1H, s); 8.66 (1H, s).
The compound 189 of table 58: use 2-phenyl-third-2-base amine, 1H NMR (CH 3CN) δ ppm:5.69 (1H, s); 7.29 (7H, m); 7.53 (1H, d); 8.00 (1H, d); 8.20 (1H, s); 8.70 (1H, s).
The compound 52 of table 58: use 2-cyano group-1-methoxyl group-third-2-base amine, 1HNMR (CH 3CN) δ ppm:3.40 (3H, d); 3.62 (1H, m); 3.70 (1H, m); 5.82 (1H, s); 7.34 (1H, m); 7.36 (1H, d); 7.52 (1H, m); 8.00 (1H, d); 8.19 (1H, s); 8.69 (1H, s).
The compound 133 of table 58: use the 4-fluoroaniline, 1H NMR (CH 3CN) δ ppm:5.91 (1H, s); 7.09 (2H, t); 7.40 (1H, s); 7.62 (3H, m); 8.02 (1H, d); 8.22 (1H, s); 8.70 (1H, s); 8.94 (1H, s).
The compound 38 of table 58: use 2-cyano group-3-methyl-Ding-2-base amine, 1H NMR (CH 3CN) δ ppm:1.00 (6H, 4xd); 1.57 (3H, 2xs); 2.36 (1H, m); 5.80 (1H, 2xs); 7.18 (1H, s); 7.32 (1H, m); 7.52 (1H, d); 8.00 (1H, d); 8.20 (1H, s); 8.70 (1H, s).
The compound 64 of table 58: use the trimethyl silyl methylamine, 1H NMR (CH 3CN) δ ppm:2.76 (2H, m); 5.75 (1H, s); 6.98 (1H, s); 7.29 (1H, s); 7.50 (1H, d); 7.99 (1H, s); 8.17 (1H, s); 8.68 (1H, s).
The compound 84 of table 58: use propargyl amine, 1H NMR (CH 3CN) δ ppm:2.43 (1H, s); 4.02 (2H, m); 5.80 (1H, s); 7.32 (1H, s); 7.52 (1H, d); 7.59 (1H, s); 7.99 (1H, d); 8.18 (1H, s); 8.68 (1H, s).
Embodiment 6
This embodiment has illustrated the preparation of 2-(3,8-dibromo quinolyl-6-oxygen)-2-methylthio group-N-(2-thienyl methyl) ethanamide (compound 124 of table 61)
Stage 1:3, the preparation of 8-two bromo-6-hydroxyquinolines
Step 1:6-amino-3, the preparation of 8-two bromoquinolines
At room temperature, with 3,8-two bromo-6-nitroquinoline (48.5g, as J Am ChemSoc (1955), 77, the described preparation of 4175-4176) be suspended in the concentrated hydrochloric acid (400ml), add iron powder (27g passes through hydrogen reducing) in batches, during adding, make temperature of reaction rise to 73 ℃.The glassy yellow suspension of Xing Chenging becomes burgundy in the final stage of reaction at first.It is 10 with aqueous sodium hydroxide solution (10M) alkalization until the pH of reaction also that mixture is cooled to 0 ℃.In suspension, add ethyl acetate,, filter by bed of diatomaceous earth then the mixture thorough mixing.Separate organic moiety, contain water section and extract once more with ethyl acetate.The insoluble substance reusable heat acetone extract that leaches from solution merges organic moiety, with sodium bicarbonate aqueous solution washing, Sodium Persulfate drying and reduction vaporization, produces 34.7g 6-amino-3, and 8-two bromoquinolines are brown solid.
1H NMR(CDCl 3)δppm：4.09(2H，s)；6.76(1H，s)；7.52(1H，s)；8.03(1H，s)；8.71(1H，s)。
Step 2:3, the preparation of 8-two bromo-6-hydroxyl-quinoline
With 6-amino-3,8-two bromoquinolines (1.1g) be suspended in the phosphoric acid (10ml) of moisture (10ml) and in the sealed glass test tube 180 ℃ of heating 4 days.Mixture is cooled to room temperature, pours in the salt solution and use ethyl acetate extraction.Organic extract persulfuric acid magnesium drying, reduction vaporization and remaining solid pass through chromatogram (silicon-dioxide; Hexane/ethyl acetate) separate, produce 0.4g 3,8-two bromo-6-hydroxyl-quinoline are the light brown solid.
1H NMR(CDCl 3)δppm：6.97(1H，s)；7.69(1H，s)；8.09(1H，s)；8.72(1H，s)。
Stage 2
With with step 1 similar methods in stage 2 of embodiment 5, make 3,8-two bromo-6-hydroxyquinolines and 2-bromo-2-methylthio group acetic acid ethyl reaction produce 2-(3,8-two bromo-quinolyl-6-oxygen)-2-methylmercaptan ethyl acetoacetic ester, are light yellow gluey thing.
1H NMR(CDCl 3)δppm：1.36(3H，t)；2.24(3H，s)；4.29-4.41(2H，m)；5.69(1H，s)；7.12(1H，d)；7.88(1H，d)；8.22(1H，d)；8.89(1H，d)。
With with step 2 similar methods in stage 2 of embodiment 5, with 2-(3,8-dibromo quinolyl-6-oxygen)-2-methylmercaptan ethyl hydrolysis of ethyl acetate, produce 2-(3,8-dibromo quinolyl-6-oxygen)-2-methylthio group acetate, be light yellow solid.
1H NMR(CDCl 3)δppm：2.26(3H，s)；5.71(1H，s)；7.17(1H，d)；7.89(1H，d)；8.27(1H，d)；8.88(1H，d)。
With with stages 2 similar methods of embodiment 1, with 2-(3,8-dibromo quinolyl-6-oxygen)-2-methylthio group acetate and condensation of 2-amino methyl thiophene, produce 2-(3,8-dibromo quinolyl-6-oxygen)-2-methylthio group-N-(2-thienyl methyl) ethanamide.
1H NMR (CH 3CN) δ ppm:(is covered by the NMR solvent at some signals of High-Field) 4.41 (2H, m); 5.80 (1H, s); 7.23 (5H, m); 7.30 (1H, s); 7.68 (1H, s); 7.90 (1H, s); 8.36 (1H, s); 8.84 (1H, s).
Following acid amides uses the similarity method preparation.
The compound 38 of table 61: use 2-cyano group-3-methyl-Ding-2-base amine, 1H NMR (CH 3CN) δ ppm:0.94-1.10 (6H, 4xd); 1.56-1.58 (3H, 2xs); 5.80 (1H, s); 7.15 (1H, s); 7.34 (1H, d); 7.94 (1H, d); 8.42 (1H, s); 8.85 (1H, s).
The compound 52 of table 61: use 2-cyano group-1-methoxyl group-third-2-base amine, 1HNMR (CH 3CN) δ ppm:3.40 (3H, d); 3.65 (2H, m); 5.81 (1H, s); 7.34 (2H, m); 7.93 (1H, d); 8.39 (1H, s); 8.84 (1H, s).
The compound 12 of table 61: use tert-butylamine, 1H NMR (CH 3CN) δ ppm:5.63 (1H, s); 6.69 (1H, s); 7.30 (1H, s); 7.92 (1H, s); 8.39 (1H, s); 8.84 (1H, s).
The compound 150 of table 61: use phenmethyl amine, 1H NMR (CH 3CN) δ ppm:4.41 (2H, m); 5.80 (1H, s); 7.23 (5H, m); 7.30 (1H, s); 7.68 (1H, s); 7.90 (1H, s); 8.36 (1H, s); 8.84 (1H, s).
The compound 211 of table 61: use N-morpholinyl hydrazine, 1H NMR (CH 3CN) δ ppm:3.59 (8H, m); 5.42 (1H, s); 6.09 (1H, s); 7.20 (1H, s); 7.86 (1H, s); 8.40 (1H, s); 8.83 (1H, s).
Embodiment 7
This embodiment has illustrated the preparation of 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group-N-(1-methoxyl group-3-methyl fourth-3-yl) ethanamide (compound 48 of table 57)
The preparation of stage 1:2-(3-bromoquinoline base-6-oxygen)-2-methylthio group acetate
Step 1
With with step 1 similar methods in stage 2 of embodiment 5, make 3-bromo-6-hydroxyquinoline (as Liebigs Ann Chem (1966), the described preparation of 98-106) with 2-bromo-2-methylthio group acetic acid ethyl reaction, produce 2-(3-bromoquinoline base-6-oxygen)-2-methylmercaptan ethyl acetoacetic ester, be light yellow gluey thing.
1H NMR(CDCl 3)δppm：1.34(3H，t)；2.24(3H，s)；4.30-4.38(2H，m)；5.70(1H，s)；7.14(1H，m)；7.48-7.52(1H，dd)；8.02(1H，d)；8.22(1H，s)；8.80(1H，s)。
Step 2
With with step 2 similar methods in stage 2 of embodiment 5, with 2-(3-bromoquinoline base-6-oxygen)-2-methylmercaptan ethyl hydrolysis of ethyl acetate, produce 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group acetate, colorless solid, m.p.166-167 ℃.
1H NMR(CDCl 3)δppm：2.26(3H，s)；5.76(1H，s)；7.20(1H，m)；7.50-7.54(1H，dd)；8.01(1H，d)；8.28(1H，s)；8.78(1H，s)。
The preparation of stage 2:1-methoxyl group-3-methyl fourth-3-base amine hydrochlorate
Under nitrogen atmosphere and room temperature, at anhydrous N, drip the N of 1-hydroxy-3-methyl fourth-3-base amine (0.52g) in the stirred solution of dinethylformamide (2ml), dinethylformamide (5ml) solution to sodium hydride (0.30g, 80% mineral oil dispersion).Mixture was stirred 3 hours, in 5 minutes, add the N of methyl iodide (0.74g), dinethylformamide (5ml) solution, and then stirred 2.25 hours and at room temperature stored 18 hours.The solution with water dilution, ethyl acetate extraction (three times) and merging extract extract with dilute hydrochloric acid then.The aqueous acidic extract reduction vaporization and with the toluene condistillation to remove remaining water, produce 1-methoxyl group-3-methyl fourth-3-base amine hydrochlorate, be yellow jelly.
1H NMR(CDCl 3)δppm：1.54(6H，s)；1.96-2.00(2H，t)；3.48(3H，s)；3.62-3.66(2H，t)。
With similar methods, make 1-hydroxy-3-methyl fourth-3-base amine and iodoethane reaction, produce 1-oxyethyl group-3-methyl fourth-3-base amine hydrochlorate.
1H NMR(CDCl 3)δppm：1.20-1.24(3H，t)；1.54(6H，s)；1.96-2.00(2H，t)；3.50(2H，q)；3.66-3.70(2H，t)。
With similar methods, make 1-hydroxy-2-methyl third-2-base amine and iodomethane reaction, produce 1-methoxyl group-2-methyl-prop-2-base amine hydrochlorate.
1H NMR(CDCl 3)δppm：1.47(6H，s)；3.43(3H，s)；3.44(2H，s)；8.24(3H bs)。
With similar methods, make 1-hydroxy-2-methyl third-2-base amine and the reaction of 4-fluorobenzene monobromomethane, produce 1-(4-fluorobenzene methoxyl group)-2-methyl-prop-2-base amine hydrochlorate.
1H NMR(CDCl 3)δppm：1.41(6H，s)；3.46(2H，s)；4.53(2H，s)；7.00-7.04(2H，m)；7.32-7.36(2H，m)；8.30(3H bs)。
Stage 3
With with stages 2 similar methods of embodiment 1, with 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group acetate and 1-methoxyl group-3-methyl fourth-3-base amine condensation, produce 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group-N-(1-methoxyl group-3-methyl fourth-3-yl) ethanamide, be light yellow solid, m.p.88-90 ℃.
1H NMR(CDCl 3)δppm：1.46(3H，s)；1.52(3H，s)；1.80-1.84(2H，q)；2.20(3H，s)；3.30(3H，s)；3.55-3.58(2H，t)；5.55(1H，s)；7.16(1H，d)；7.43-7.46(1H，dd)；7.90(1H，s)；8.02-8.05(1H，d)；8.24(1H，s)；8.80(1H，s)。
Following acid amides uses the similarity method preparation.
The compound 12 of table 57: use tert-butylamine, 1H NMR (CDCl 3) δ ppm:1.43 (9H, s); 2.20 (3H, s); 5.58 (1H, s); 6.43 (1H, s); 7.18 (1H, d); 7.44-7.48 (1H, dd); 8.03-8.05 (1H, d); 8.24 (1H, s); 8.82 (1H, s).
The compound 65 of table 57: use 1-t-butyldimethylsilyloxy base-2-methyl-prop-2-base amine, light yellow oil, 1H NMR (CDCl 3) δ ppm:0.06 (3H, s); 0.08 (3H, s); 0.88 (9H, s); 1.38 (3H, s); 1.42 (3H, s); 2.18 (3H, s); 3.47-3.53 (2H, q); 5.59 (1H, s); 6.98 (1H, s); 7.16 (1H, d); 7.41-7.45 (1H, dd); 8.02-8.04 (1H, d); 8.24 (1H, s); 8.81 (1H, s).
The compound 50 of table 57: use 1-methylthio group-2-methyl-prop-2-base amine, light yellow oil, 1HNMR (CDCl 3) δ ppm:1.46 (3H, s); 1.48 (3H, s); 2.16 (3H, s); 2.22 (3H, s); 2.94-3.02 (2H, dd); 5.60 (1H, s); 6.72 (1H, s); 7.20 (1H, d); 7.46-7.48 (1H, dd); 8.04-8.06 (1H, d); 8.24 (1H, d); 8.81 (1H, d).
The compound 47 of table 57: use 1-methoxyl group-2-methyl-prop-2-base amine, colorless solid, m.p.90-91 ℃, 1H NMR (CDCl 3) δ ppm:1.40 (3H, s); 1.44 (3H, s); 2.20 (3H, s); 3.36-3.48 (2H, dd); 3.49 (3H, s); 5.59 (1H, s); 6.77 (1H, s); 7.18 (1H, d); 7.44-7.48 (1H, dd); 8.03-8.07 (1H, d); 8.26 (1H, d); 8.81 (1H, s).
The compound 49 of table 57: use 1-oxyethyl group-3-methyl fourth-3-base amine, colorless solid, m.p.111-113 ℃, 1H NMR (CDCl 3) δ ppm:1.18-1.22 (3H, t); 1.46 (3H, s); 1.51 (3H, s); 1.78-1.84 (2H, m); 2.21 (3H, s); 3.44-3.50 (2H, q); 3.56-3.64 (2H, m); 5.53 (1H, s); 7.17 (1H, d); 7.44-7.46 (1H, dd); 7.82 (1H, s); 8.03-8.05 (1H, d); 8.25 (1H, s); 8.81 (1H, s).
The compound 40 of table 57: use 1-hydroxy-3-methyl fourth-3-base amine, colorless solid m.p.124-126 ℃, 1H NMR (CDCl 3) δ ppm:1.48 (3H, s); 1.51 (3H, s); 1.84-1.92 (2H, m); 2.20 (3H, s); 3.86-3.89 (2H, t); 5.56 (1H, s); 7.14 (1H, d); 7.42-7.44 (1H, dd); 7.75 (1H, s); 8.00-8.03 (1H, d); 8.24 (1H, d); 8.80 (1H, d).
The compound 198 of table 57: use 1-(4-fluorobenzene methoxyl group)-2-methyl-prop-2-base amine, colorless solid m.p.124-126 ℃, 1H NMR (CDCl 3) δ ppm:1.42 (3H, s); 1.44 (3H, s); 2.16 (3H, s); 3.44-3.56 (2H, dd); 4.52 (2H, m); 5.58 (1H, s); 6.82 (1H, bs); 6.98-7.02 (2H, m); 7.13 (1H, d); 7.24-7.28 (2H, m); 7.34-7.38 (1H, dd); 8.00-8.02 (1H, d); 8.20 (1H, d); 8.80 (1H, d).
The compound 89 of table 57: use 1-cyano group-cyclopropylamine (O ' Donnell etc., Synthesis(1984), 127), cream-colored solid, 178 ℃ of mp, 1H NMR (CDCl 3) δ ppm:2.13 (3H, s); 4.48-4.64 (2H, 4xd); 5.57 (1H, s); 6.86 (1H, s); 6.92 (1H, s); 7.08 (1H, t); 7.30-7.38 (5H, m).
The compound 4 of table 57: use diethylamide, jelly, 1H NMR (CDCl 3) δ ppm:1.15 (3H, t); 1.23 (3H, t); 2.29 (3H, s); 3.34 (1H, m); 3.50 (1H, m); 3.58 (2H, m); 5.83 (1H, s); 7.17 (1H, s); 7.51 (1H, d); 8.00 (1H, d); 8.22 (1H, s); 8.78 (1H, s).
The compound 2 of table 57: use dimethyl amine, cream-colored solid, m.p.158-161 ℃.
The compound 27 of table 57: use 3,3,3-three fluoro-2-methyl-prop-2-base amine, light yellow solid, 112 ℃ of mp.
The compound 88 of table 57: use N, N-two cyclopropylamine, colorless solid, m.p.122 ℃, 1HNMR (CDCl 3) δ ppm:0.6-1.15 (8H, m); 2.21 (3H, s); 2.61 (1H, m); 2.80 (1H, m); 6.38 (1H, s); 7.17 (1H, d); 7.52 (1H, dd); 8.00 (1H, d); 8.20 (1H, d); 8.80 (1H, d).
The compound 60 of table 57: use 2-amino-2-methyl methyl propionate, the spumescence solid, 1HNMR (CDCl 3) δ ppm:1.69 (3H, s); 1.70 (3H, s); 2.26 (3H, s); 3.83 (3H, s); 5.70 (1H, s); 7.25 (1H, d); 7.35 (1H, s); 7.54 (1H, dd); 8.10 (1H, d); 8.30 (1H, d); 8.87 (1H, d).
The compound 64 of table 57: use the trimethyl silyl methylamine, 1H NMR (CH 3CN) δ ppm:0.28 (9H, s); 3.04 (2H, s); 6.05 (1H, s); 7.28 (1H, s); 7.57 (1H, s); 7.79 (1H, d); 8.26 (1H, d); 8.64 (1H, s); 9.06 (1H, s).
The compound 124 of table 57: use thienyl methyl amine, 1H NMR (CH 3CN) δ ppm:4.58 (2H, m); 5.78 (1H, s); 6.89 (1H, t); 6.96 (1H, s); 7.22 (1H, d); 7.27 (1H, s); 7.50 (1H, d); 7.78 (1H, s); 7.96 (1H, d); 8.32 (1H, s); 8.76 (1H, s).
The compound 35 of table 57: use 2-cyano group-third-2-base amine, 1H NMR (CH 3CN) δ ppm:1.67 (3H, s); 1.69 (3H, s); 5.79 (1H, s); 7.31 (1H, s); 7.38 (1H, s); 7.55 (1H, d); 7.98 (1H, d); 8.37 (1H, s); 8.77 (1H, s).
The compound 133 of table 57: use the 4-fluoroaniline, 1H NMR (CDCl 3) δ ppm:2.26 (3H, s); 5.82 (1H, s); 7.06 (2H, t); 7.26 (1H, m); 7.52 (1H, m); 7.60 (2H, m); 8.06 (1H, d); 8.26 (1H, d); 8.34 (1H, s); 8.82 (1H, s).
The compound 111 of table 57: use 2-cyclohexenyl-ethylamine, 1H NMR (CH 3CN) δ ppm:3.47 (4H, m); 5.58 (1H, s); 5.89 (1H, s); 7.25 (1H, m); 7.44 (1H, s); 7.66 (1H, d); 8.13 (1H, d); 8.51 (1H, s); 8.92 (1H, s).
The compound 150 of table 57: use phenmethyl amine, 1H NMR (CH 3CN) δ ppm:4.42 (2H, m); 5.80 (2H, s); 7.25 (6H, m); 7.52 (1H, d); 7.71 (1H, s); 7.96 (1H, d); 8.32 (1H, s); 8.76 (1H, s).
The compound 38 of table 57: use 2-cyano group-3-methyl-Ding-2-base amine, 1H NMR (CH 3CN) δ ppm:1.00 (6H, 4xd); 1.57 (3H, 2xs); 2.38 (1H, m); 5.80 (1H, 2xs); 7.29 (1H, s); 7.31 (1H, m); 7.54 (1H, d); 7.99 (1H, d); 8.37 (1H, s); 8.77 (1H, s).
The compound 120 of table 57: use thiazol-2-yl amine, 1H NMR (CH 3CN) δ ppm:6.08 (1H, s); 7.12 (1H, s); 7.38 (1H, d); 7.46 (1H, s); 7.62 (1H, d); 8.00 (1H, d); 8.39 (1H, s); 8.78 (1H, s).
The compound 122 of table 57: use furfuryl group amine, 1H NMR (CH 3CN) δ ppm:4.42 (2H, m); 5.79 (1H, s); 6.22 (1H, s); 6.31 (1H, s); 7.28 (1H, s); 7.36 (1H, s); 7.50 (1H, d); 7.63 (1H, s); 7.95 (1H, d); 8.32 (1H, s); 8.75 (1H, s).
The compound 52 of table 57: use 2-cyano group-1-methoxyl group-third-2-base amine, 1HNMR (CDCl 3) δ ppm:1.82 (3H, 2xs); 2.20 (3H, s); 3.52 (3H, 2xs); 3.66 (1H, m); 3.78 (1H, m); 5.72 (1H, 2xs); 7.15 (1H, 2xs); 7.20 (1H, m); 7.46 (1H, m); 8.06 (1H, d); 8.26 (1H, s); 8.82 (1H, d).
The compound 84 of table 57: use propargyl amine, 1H NMR (CH 3CN) δ ppm:2.43 (1H, s); 4.00 (2H, m); 5.79 (1H, s); 7.30 (1H, s); 7.52 (1H, d); 7.60 (1H, s); 7.98 (1H, d); 8.36 (1H, s); 8.76 (1H, s).
The compound 189 of table 57: use 2-phenyl-third-2-base amine, 1H NMR (CH 3CN) δ ppm:1.60 (3H, s); 1.66 (3H, s); 5.69 (1H, s); 7.16 (1H, t); 7.27 (6H, m); 7.36 (1H, d); 7.54 (1H, d); 7.98 (1H, d); 8.36 (1H, s); 8.77 (1H, s).
The compound 70 of table 57: use allyl amine, 1H NMR (CH 3CN) δ ppm:3.86 (2H, t); 5.06 (1H, d); 5.14 (1H, d); 5.79 (1H, s); 5.84 (1H, m); 7.32 (1H, s); 7.38 (1H, s); 7.52 (1H, d); 7.98 (1H, d); 8.35 (1H, s); 8.76 (1H, s).
Embodiment 8
This embodiment has illustrated the preparation of 2-(3-fluorine quinolyl-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 59)
The preparation of stage 1:3-fluoro-6-hydroxyquinoline
The preparation of step 1:3-amino-6-methoxy quinoline
Under nitrogen atmosphere, [synthetic method is in Tetrahedron (1986) to 3-bromo-6-methoxy quinoline, 42, provide among the 1475-1485] (2.38g), three (dibenzalacetones), two palladiums (0) (0.114g) and add two trimethyl silyl amination lithium (11.0ml, the 1.0M solution in hexane) solution in tri-butyl phosphine a tetrafluoro borate (0.116g) the stirring the mixture in toluene (15ml).Mixture was stirred 2 days, and brown suspension merges acidic moiety with the ether dilution and with 2M aqueous hydrochloric acid extraction (twice), with the ether washing,, produce the product that needs with the alkalization of 2M aqueous sodium hydroxide solution, be brown solid, use it for next step and need not to be further purified.
1H NMR(CDCl 3)δppm：3.90(3H，s)；6.87(1H，d)；7.10(1H，dd)；7.16(1H，d)；7.85(1H，d)；8.35(1H，d)。
The preparation of step 2:3-fluoro-6-methoxy quinoline
Under nitrogen atmosphere, stir the interpolation 3-amino-solution of 6-methoxy quinoline (1.05g) in anhydrous methylene chloride (15ml) to-12 ℃ boron-trifluoride etherates (1.29g).Yellow suspension was stirred 15 minutes, drip the solution of nitrite tert-butyl (0.74g) in methylene dichloride (5ml) then.Mixture was stirred 2 hours at 0 ℃, add 1 then, the 2-dichlorobenzene with mixture heating up to 73 ℃, makes methylene dichloride distill from reaction vessel gradually, is warming up to 90 ℃ then to finish reaction.Make mixture be cooled to room temperature, with the methylene dichloride dilution, wash with water, persulfuric acid magnesium drying is filtered reduction vaporization then, produces black oil, and it is passed through chromatogram (silicon-dioxide; Hexane/ethyl acetate) separates, produce 0.54g oil, wherein contain the product of needs.MH +178
Step 3
Under nitrogen atmosphere, with the product of step 2 (0.45g) and pyridine hydrochloride (4.5g) 200 ℃ of fusions 3 hours.Mixture is cooled to room temperature, and dilute with water is also used ethyl acetate extraction.Extract persulfuric acid magnesium drying is filtered and reduction vaporization, produces the product that needs, and is the light brown solid.MH +164
The preparation of stage 2:3-fluorine quinolyl-6-oxygen-2-methylmercaptan ethyl acetoacetic ester
With with step 1 similar methods in stage 2 of embodiment 5, make 3-fluoro-6-hydroxyquinoline and 2-bromo-2-methylthio group acetic acid ethyl reaction, produce 2-(3-fluorine quinolyl-6-oxygen)-2-methylmercaptan ethyl acetoacetic ester, be colorless solid.
1H NMR(CDCl 3)δppm：1.36(3H，t)；2.25(3H，s)；4.29-4.40(2H，m)；5.71(1H，s)；7.20(1H，d)；7.47(1H，dd)；7.71(1H，dd)；8.11(1H，d)；8.71(1H，d)。
With with step 2 similar methods in stage 2 of embodiment 5, with 2-(3-fluorine quinolyl-6-oxygen)-2-methylmercaptan ethyl hydrolysis of ethyl acetate, produce 2-(3-fluorine quinolyl-6-oxygen)-2-methylthio group acetate, be colorless solid.
1H NMR(CDCl 3)δppm：2.20(3H，s)；4.0(1H，bs)；5.69(1H，s)；7.19(1H，d)；7.39(1H，dd)；7.68(1H，dd)；7.96(1H，d)；8.62(d)。
With with stages 2 similar methods of embodiment 1, with 2-(3-fluorine quinolyl-6-oxygen)-2-methylthio group acetate and tert-butylamine condensation, produce 2-(3-fluorine quinolyl-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide, be colourless jelly.
1H NMR(CDCl 3)δppm：1.43(9H，s)；2.20(3H，s)；5.60(1H，s)；6.45(1H，s)；7.22(1H，d)；7.41(1H，dd)；7.71(1H，dd)；8.08(1H，d)；8.72(1H，d)。
The compound 52 of table 59: with similar methods, with 2-(3-fluorine quinolyl-6-oxygen)-2-methylthio group acetate and 2-cyano group-1-methoxy propyl-2-base amine condensation, produce 2-(3-fluorine quinolyl-6-oxygen)-2-methylthio group-N-(2-cyano group-1-methoxy propyl-2-yl) ethanamide, be colourless jelly.
1H NMR (CDCl 3) δ ppm:1.79 and 1.81 (3H, s); 2.22 (3H, s); 3.49 and 3.53 (3H, s); 3.67 (1H, d); 3.74 and 3.81 (1H, d); 5.71 and 5.74 (1H, s); 7.12 and 7.18 (1H, s); 7.26 (1H, d); 7.41 (1H, dd); 7.72 (1H, d); 8.10 (1H, d); 8.73 (1H, d), consistent with 1: 1 non-enantiomer mixture.
Embodiment 9
This embodiment has illustrated the preparation of 2-(methylthio group)-2-(3-bromoquinoline base-6-oxygen)-N-E-(4-phenyl-2-methylpent-3-alkene-2-yl) ethanamide (compound 82 of table 57) and 2-(methylthio group)-2-(3-phenylquinoline base-6-oxygen)-N-E-(4-phenyl-2-methylpent-3-alkene-2-yl) ethanamide (compound 82 of table 65)
With with stages 2 similar methods of embodiment 1, with 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group acetate and 4-amino-4-methylpent-2-alkynes condensation, produce 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group-N-(2-methylpent-3-alkynes-2-yl) ethanamide, be colorless solid, m.p.135-137 ℃.
1H NMR(CDCl 3)δppm：1.70(3H，s)；1.71(3H，s)；1.83(3H，s)；2.22(3H，s)；5.62(1H，s)；6.72(1H，s)；7.18(1H，d)；7.47(1H，dd)；8.05(1H，d)；8.24(1H，d)；8.82(1H，m)。
Under nitrogen atmosphere, with 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group-N-(2-methylpent-3-alkynes-2-yl) ethanamide (0.200g), three-(dibenzalacetone) two-palladium (0) (0.007g), phenyl-boron dihydroxide (0.060g), tri-butyl phosphine a tetrafluoro borate (0.006g), cesium fluoride (0.245g) be in deoxidation 1, the mixture in the 4-dioxane (10ml) at room temperature stirred 18 hours.Mixture is by diatomite filtration, and ethyl acetate extraction is used in the filtrate water dilution, separates organic phase, uses the salt water washing, and persulfuric acid magnesium drying and reduction vaporization produce jelly.This glue is by chromatogram (silicon-dioxide; Hexane: 1: 4 to 1: 1 volume ratio of ethyl acetate) separate, produce 0.034g 2-(methylthio group)-2-(3-bromoquinoline base-6-oxygen)-N-E-(4-phenyl-2-methylpent-3-alkene-2-yl) ethanamide, be colourless jelly.
1H NMR(CDCl 3)δppm：1.67(6H，s)；2.10(3H，s)；2.24(3H，s)；5.63(1H，s)；5.911H，s)；6.75(1H，s)；7.25-7.35(6H，m)；7.46(1H，d)；8.06(1H，d)；8.23(1H，s)；8.81(1H，s)；
With 0.012g 2-(methylthio group)-2-(3-phenylquinoline base-6-oxygen)-N-E-(4-phenyl-2-methylpent-3-alkene-2-yl) ethanamide, be colourless jelly.
1H NMR(CDCl 3)δppm：1.67(6H，s)；2.10(3H，s)；2.26(3H，s)；5.67(1H，s)；5.92(1H，s)；6.81(1H，s)；7.25-7.35(6H，m)；7.46(2H，m)；7.53(2H，m)；7.70(2H，m)；8.10(1H，d)；8.22(1H，s)；9.10(1H，s)。
Embodiment 10
This embodiment has illustrated the preparation of 2-(methylthio group)-2-(3-[4-pyridyl] quinolyl-6-oxygen)-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 68)
Under nitrogen atmosphere, with 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide (0.10g), three-(dibenzalacetone) two-palladium (0) (0.004g), pyridine-4-boric acid (0.032g), tri-butyl phosphine a tetrafluoro borate (0.003g), cesium fluoride (0.13g) be in deoxidation 1, the mixture in the 4-dioxane (10ml) at room temperature stirred 18 hours.In mixture, add (four) triphenyl phosphine palladium (0) (0.005g) and yellow soda ash (0.100g), reaction is heated to 100 ℃, lasting 6 hours, at room temperature stored then 18 hours.Mixture is by diatomite filtration, and ethyl acetate extraction is used in the filtrate water dilution, separates organic phase, uses the salt water washing, and persulfuric acid magnesium drying and reduction vaporization produce jelly.This glue is by chromatogram (silicon-dioxide; Hexane: ethyl acetate) separate, produce the product that needs, 0.010g is colorless solid m.p.132-134 ℃.
1H NMR(CDCl 3)δppm：1.44(9H，s)；2.22(3H，s)；5.63(1H，s)；6.46(1H，s)；7.37(1H，s)；7.54(1H，d)；7.70(2H，m)；8.17(1H，d)；8.35(1H，s)；8.79(2H，m)；9.11(1H，s)。
The compound 12 of table 65: with similar methods, make the reaction of 2-(3-bromoquinoline base-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide and phenyl-boron dihydroxide, produce 2-(3-phenylquinoline base-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide, be cream-colored solid, m.p.134-137 ℃.
1H NMR(CDCl 3)δppm：1.44(9H，s)；2.22(3H，s)；5.63(1H，s)；6.49(1H，s)；7.35-7.40(2H，m)；7.46(2H，m)；7.54(2H，m)；7.72(1H，d)；8.14(1H，d)；8.26(1H，s)；9.10(1H，s)。
Embodiment 11
This embodiment has illustrated the preparation of 2-(3-bromoquinoline base-6-oxygen)-2-(methylthio group)-N-(1-hydroxy-2-methyl third-2-yl) ethanamide (compound 39 of table 57)
At 0-5 ℃, in 2-(3-bromoquinoline base-6-oxygen)-2-(methylthio group)-N-(1-(t-butyldimethylsilyloxy the base)-2-methyl-prop-2-yl) stirred solution of ethanamide (0.67g) in tetrahydrofuran (THF) (10ml), drip tetrabutyl ammonium fluoride (2.38ml, tetrahydrofuran solution 1M).Mixture was stirred 0.5 hour at 0 ℃, heat to room temperature restir 3 hours then.With solvent removed under reduced pressure, resistates is handled with aqueous ammonium chloride solution, uses ethyl acetate extraction, organic phase salt water washing, and persulfuric acid magnesium drying and reduction vaporization produce solid.This solid is by chromatogram (silicon-dioxide; Ethyl acetate) separates, produce the product that 0.34g needs, be colorless solid, m.p.155-157 ℃.
1H NMR(CDCl 3)δppm：1.36(3H，s)；1.40(3H，s)；2.20(3H，s)；3.66-3.70(2H，m)；3.89-3.92(1H，t)；5.64(1H，s)；6.70(1H，s)；7.20(1H，d)；7.44-7.48(1H，dd)；8.02-8.06(1H，d)；8.24(1H，s)；8.82(1H，s)。
Embodiment 12
This embodiment has illustrated the preparation of 2-(dibenzofuran group-2-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 50)
The preparation of step 1:2-(dibenzofuran group-2-oxygen)-2-methylmercaptan ethyl acetoacetic ester
Under nitrogen atmosphere and room temperature, in 40 minutes to sodium hydride (6.6g, 80% dispersion in mineral oil), adds 2-hydroxyl diphenylene-oxide (36.8g) in the stirred suspension in the dinethylformamide (25ml) at N, the solution in the dinethylformamide (150ml) at anhydrous N.Mixture was stirred 3.25 hours, dripped 2-bromo-2-methylmercaptan ethyl acetoacetic ester (54.2g, 90% is pure) then at N in 20 minutes, the solution in the dinethylformamide (50ml) makes temperature of reaction rise to 47 ℃ during this period.Add when finishing, mixture was stirred 21.5 hours, pour in the water also with extracted with diethyl ether (three times).Merge extract, with dilute sodium hydroxide aqueous solution washing (twice), water washing (three times), persulfuric acid magnesium drying and reduction vaporization then.Resistates is by chromatogram (silicon-dioxide; Diethyl ether: hexane, 1: 2 to 1: 1 volume ratio) separate, produce tangerine look oil, 33g wherein contains the product of needs, can be used for next stage, need not to be further purified.The sample of oil is further purified by chromatogram, obtains analyzing samples.
1H NMR(CDCl 3)δppm：1.34-1.38(3H，t)；2.26(3H，s)；4.30-4.38(2H，m)；5.64(1H，s)7.16-7.20(1H，dd)；7.32-7.36(1H，dd)；7.44-7.60(4H，m)；7.92-7.94(1H，d)。
The preparation of step 2:2-(dibenzofuran group-2-oxygen)-2-methylthio group acetate
At room temperature, in 2-(dibenzofuran group-2-the oxygen)-stirred solution of 2-methylmercaptan ethyl acetoacetic ester (15.8g) in tetrahydrofuran (THF) (250ml), add water (25ml) solution of sodium hydroxide (2.5g).Mixture stirred 2 hours and reduction vaporization to remove tetrahydrofuran (THF).Residue diluted with water with ether washing (twice) and water concentrated hydrochloric acid acidifying, is used ethyl acetate extraction (three times) then.Merge extract, use the salt water washing, persulfuric acid magnesium drying is filtered and reduction vaporization, produces yellow solid, also filters with the washed with dichloromethane of a little volume, obtains 5.90g 2-(dibenzofuran group-2-oxygen)-2-methylthio group acetate, is cream-colored solid.
1H NMR(DMSO-d 6)δppm：2.16(3H，s)；6.02(1H，s)7.22-7.26(1H，dd)；7.38-7.42(1H，dd)；7.50-7.54(1H，dd)；7.64-7.70(2H，m)；7.90(1H，m)；8.10-8.14(1H，d)。
Step 3
With with stages 2 similar methods of embodiment 1, with 2-(dibenzofuran group-2-oxygen)-2-methylthio group acetate and tert-butylamine condensation, produce the product that needs.
1H NMR (CH 3CN) some signals of δ ppm:(High-Field are covered by the NMR solvent) 5.56 (1H, s); 6.74 (1H, s); 7.20 (1H, d); 7.35 (1H, t); 7.48 (1H, t); 7.56 (2H, m); 7.70 (1H, s); 7.98 (1H, d).
Following acid amides uses the similarity method preparation.
The compound 52 of table 50: use 2-cyano group-1-methoxyl group-third-2-base amine, 1HNMR (CH 3CN) δ ppm:3.40 (3H, 2xs); 3.64 (1H, m); 3.72 (1H, 2xs); 5.74 (1H, 2xs); 7.22 (1H, d); 7.36 (2H, m); 7.48 (1H, t); 7.56 (2H, m); 7.72 (1H, s); 8.00 (1H, d).
The compound 84 of table 50: use propargyl amine, 1H NMR (CH 3CN) δ ppm:2.44 (1H, s); 4.03 (2H, m); 5.72 (1H, s); 7.22 (1H, dd); 7.36 (1H, t); 7.49 (1H, t); 7.56 (3H, m); 7.71 (1H, s); 8.00 (1H, d).
The compound 70 of table 50: use allyl amine, 1H NMR (CH 3CN) δ ppm:3.88 (2H, t); 5.07 (1H, d); 5.16 (1H, d); 5.16 (1H, d); 5.72 (1H, s); 5.88 (1H, m); 7.22 (1H, dd); (7.36 2H, t s); 7.49 (1H, t); 7.56 (3H, m); 7.71 (1H, s); 8.00 (1H, d).
The compound 189 of table 50: use 2-phenyl-third-2-base amine, 1H NMR (CH 3CN) δ ppm:5.62 (1H, s); 7.16 (1H, t); 7.25 (4H, m); 7.38 (3H, m); 7.50 (1H, t); 7.58 (2H, m); 7.71 (1H, s); 8.00 (1H, d).
The compound 120 of table 50: use thiazol-2-yl amine, 1H NMR (CH 3CN) δ ppm:6.00 (1H, s); 7.12 (1H, s); 7.31 (1H, d); 7.37 (1H, t); 7.48 (2H, m); 7.58 (2H, m); 7.80 (1H, s); 8.02 (1H, d).
The compound 122 of table 50: use furfuryl group amine, 1H NMR (CH 3CN) δ ppm:4.44 (2H, dq); 5.72 (1H, s); 6.24 (1H, s); 6.32 (1H, s); 7.20 (1H, d); 7.36 (2H, m); 7.54 (3H, m); 7.63 (1H, s); 7.70 (1H, s); 7.99 (1H, d).
The compound 133 of table 50: use the 4-fluoroaniline, 1H NMR (CH 3CN) δ ppm:5.83 (1H, s); 7.09 (2H, t); 7.30 (1H, d); 7.36 (1H, t); 7.49 (1H, t); 7.58 (2H, m); 7.65 (2H, m); 7.80 (1H, s); 8.02 (1H, d); 8.96 (1H, s).
The compound 128 of table 50: use the 2-cyano-aniline, 1H NMR (CH 3CN) δ ppm:5.94 (1H, s); 7.35 (4H, m); 7.50 (1H, t); 7.58 (1H, d); 7.68 (1H, t); 7.74 (1H, d); 7.83 (1H, s); 7.95 (1H, d); 8.02 (1H, s); 9.22 (1H, s).
The compound 38 of table 50: use 2-cyano group-3-methyl-Ding-2-base amine, 1H NMR (CH 3CN) δ ppm:1.04 (6H, 4xd); 2.41 (1H, m); 5.72 (1H, s); 7.22 (2H, d); 7.36 (1H, t); 7.49 (1H, t); 7.56 (2H, m); 7.70 (1H, s); 8.01 (1H, d).
The compound 35 of table 50: use 2-cyano group-third-2-base amine, 1H NMR (CH 3CN) δ ppm:5.72 (1H, s); 7.24 (1H, d); 7.37 (2H, m); 7.49 (1H, t); 7.56 (2H, m); 7.72 (1H, s); 8.00 (1H, d).
Embodiment 13
This embodiment has illustrated the preparation of 2-(3-bromo-8-toluquinoline base-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 72)
The preparation of stage 1:3-bromo-6-hydroxyl-8-toluquinoline
6-amino-3-bromo-8-toluquinoline (12g) is suspended in the mixture of water (5ml) and phosphoric acid (60ml) and in the sealed glass test tube, is heated to 180 ℃, continue 3 days.Mixture is cooled to room temperature, and dilute with water uses aqueous sodium hydroxide solution (2M) to be adjusted to pH 3-4 then.The precipitation that forms is leached from solution, and with cold water washing with absorb water to driedly, generation 11.0g 3-bromo-6-hydroxyl-8-toluquinoline is gray solid.
1H NMR(d6-DMSO)δppm：2.56(3H，s)；3.50(1H，bs)；6.91(1H，d)；7.15(1H，d)；8.38(1h，d)；8.61(1H，d)。
The preparation of stage 2:2-(3-bromo-8-toluquinoline base-6-oxygen)-2-methylmercaptan ethyl acetoacetic ester
With with step 1 similar methods in stage 2 of embodiment 5, make 3-bromo-8-methyl-6-hydroxyquinoline and 2-chloro-2-methylthio group acetic acid ethyl reaction, produce 2-(3-bromo-8-toluquinoline base-6-oxygen)-2-methylmercaptan ethyl acetoacetic ester, be light yellow oil.
1H NMR(CDCl 3)δppm：1.36(3H，t)；2.23(3H，s)；2.76(3H，s)；4.27-4.40(2H，m)；5.69(1H，s)；6.97(1H，d)；7.37(1H，d)；8.18(1H，d)；8.80(1H，d)。
With with step 2 similar methods in stage 2 of embodiment 5, with 2-(3-bromo-8-toluquinoline base-6-oxygen)-2-methylmercaptan ethyl hydrolysis of ethyl acetate, produce 2-(3-bromo-8-toluquinoline base-6-oxygen)-2-methylthio group acetate, be Off-white solid.
1H NMR(CDCl 3)δppm：2.22(3H，s)；2.71(3H，s)；5.68(1H，s)；6.97(1H，d)；7.34(1H，d)；8.17(1H，d)；8.75(1H，d)。
With with stages 2 similar methods of embodiment 1, with 2-(3-bromo-8-toluquinoline base-6-oxygen)-2-methylthio group acetate and tert-butylamine condensation, produce 2-(3-bromo-8-toluquinoline base-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide.
1H NMR(CDCl 3)δppm：1.43(9H，s)；2.20(3H，s)；2.78(3H，s)；5.58(1H，s)；6.42(1H，s)；7.01(1H，d)；7.32(1H，d)；8.21(1H，d)；8.82(1H，d)。
Embodiment 13A
This embodiment has illustrated the preparation of 2-(3-iodo-quinolyl-6-oxygen)-2-methylthio group-N-(2-methyl-prop-2-yl) ethanamide (compound 12 of table 58A)
The preparation of step 1:3-iodo-6-hydroxyquinoline
In the test tube of sealing, (preparation method is described in LiebigsAnn Chem (1966) to 3-bromo-6-hydroxyquinoline, 98-106) (1.0g), sodium iodide (1.34g) and cupric iodide (0.09g) the middle N of interpolation that stirs the mixture in dioxane (6.5ml), N, N ', N '-tetramethyl--ethane-1,2-diamines (0.1ml).Mixture stirs 12h at 120 ℃, in cooling, uses ammoniacal liquor, then handles with aqueous hydrochloric acid.Use ethyl acetate extraction, organic phase persulfuric acid magnesium drying is filtered and reduction vaporization, produces the product (MH that needs +272), be light brown powder, former state is used for next step.
The step 2:N-tertiary butyl-2-(3-iodo-quinoline-6-base oxygen)-2-methylthio group (sulfanyl)- The preparation of ethanamide
With with step 1 similar methods in stage 2 of embodiment 5, make 3-iodine 6-hydroxyquinoline and chloro-methyl sulfane base-acetic acid ethyl reaction, produce (3-iodo-quinoline-6-base oxygen)-methyl sulfane base-ethyl acetate, be yellow solid.
With with step 2 similar methods in stage 2 of embodiment 5, will (3-iodo-quinoline-6-base oxygen)-methyl sulfenyl-hydrolysis of ethyl acetate, produce (3-iodo-quinoline-6-base oxygen)-methylthio group-acetate, be yellow solid (MH +376).
With with stages 2 similar methods of embodiment 1, will (3-iodo-quinoline-6-base oxygen)-methylthio group-acetate and tert-butylamine condensation, produce the N-tertiary butyl-2-(the basic oxygen of 3-iodo-quinoline-6-)-2-methylthio group-ethanamide, be white solid (MH +431).
1H NMR(CDCl 3)δppm：1.41(9H，s)；2.20(3H，s)；5.58(1H，s)；6.42(1H，s)；7.12(1H，d)；7.45(1H，dd)；8.02(1H，d)，8.47(1H，d)；8.92(1H，d)。
The compound 52 of table 58A prepares with 2-cyano group-1-methoxyl group-third-2-base amine according to similar methods.
Embodiment 13B
This embodiment has illustrated the preparation of 2-(3-bromo-8-fluoro-quinoline-6-base the oxygen)-N-tertiary butyl-2-methylthio group-ethanamide (compound 12 of table 62B)
The preparation of stage 1:3-bromo-8-fluoro-quinoline-6-alcohol
The preparation of step 1:3-bromo-8-fluoro-6-methoxy yl-quinoline
In 40 minutes, with about 5 ℃ 3-bromo-6-methoxy yl-quinoline-(preparation method is described in Journal of Pharmaceutical Sciences (1984) to 8-base amine, 73 (12), among the 1854-6) (5.0g) mixture in 20ml fluoroboric acid (the 50wt% aqueous solution) is with nitrite (1.9g is in 3ml water) solution-treated.Reaction mixture at room temperature stirred 2 hours, washed with sedimentation and filtration and with cold ether afterwards.In 1.5 hours, with gained brown ceramic powder portion-wise addition in the dichlorobenzene of heat.And then 190 ℃ continue to be stirred 30 minutes again.When being cooled to room temperature, dilute with the dilute hydrochloric acid treating mixture and with ethyl acetate.Organic phase is washed with dilute sodium hydroxide, and the Sodium Persulfate drying is filtered and reduction vaporization, produces black oil, by chromatogram (silicon-dioxide; Cyclohexane/ethyl acetate) separates, produce the product (M+256) that needs.
1H NMR(CDCl3)δppm：3.88(3H，s)；6.70(1H，s)；7.04(1H，dd)；8.10(1H，s)；8.72(1H，d)。
Step 2
Step 1 products therefrom (1.5g) and Hydrogen bromide (the 48wt% aqueous solution) mixture (6.8ml) were refluxed 62 hours.Mixture is cooled to room temperature, and (2M) handles and uses ethyl acetate extraction with sodium hydroxide.Extract Sodium Persulfate drying is filtered and reduction vaporization, produces the product that needs, 3-bromo-8-fluoro-quinoline-6-alcohol, (M+242). 1H NMR(DMSO)δppm：6.93(1H，d)；7.05(1H，dd)；8.52(1H，dd)；8.66(1H，d)；10.52(1H，s)。
Stage 2:2-(3-bromo-8-fluoro-quinoline-6-base the oxygen)-N-tertiary butyl-2-methylthio group-ethanamide Preparation
With with step 1 similar methods in stage 2 of embodiment 5, make 3-bromo-8-fluoro-quinoline-6-alcohol and chloro-methyl sulfenyl-acetic acid ethyl reaction, produce (3-bromo-8-fluoro-quinoline-6-base oxygen)-methylthio group-ethyl acetate.
1H NMR(CDCl3)δppm：1.35(3H，t)；2.25(3H，s)；4.30-4.40(2H，m)；5.69(1H，s)；6.96(1H，d)；7.26(1H，dd)；8.24(1H，dd)；8.83(1H，d)。
With with step 2 similar methods in stage 2 of embodiment 5, will (3-bromo-8-fluoro-quinoline-6-base oxygen)-methylthio group-hydrolysis of ethyl acetate, produce 3-bromo-8-fluoro-quinoline-6-base oxygen)-methylthio group-acetate (M +348).
With with stages 2 similar methods of embodiment 1, with 3-bromo-8-fluoro-quinoline-6-base oxygen)-methylthio group-acetate and tert-butylamine condensation, produce 2-(the basic oxygen of 3-bromo-8-fluoro-quinoline-6-)-N-tertiary butyl-2-methylthio group-ethanamide (M +403).
1H NMR(CDCl3)δppm：1.42(9H，s)；2.20(3H，s)；5.58(1H，s)；6.45(1H，s)；6.99(1H，d)；7.20(1H，dd)；8.28(1H，dd)；8.85(1H，d)。
The compound 52 of table 62B prepares with 2-cyano group-1-methoxyl group-third-2-base amine according to similar method.
Embodiment 13C
This embodiment has illustrated the preparation of the N-tertiary butyl-2-(3-iodo-8-methyl-quinoline-6-base oxygen)-2-methylthio group-ethanamide (compound 12 of table 72A)
The preparation of step 1:3-iodo-8-methyl-quinoline-6-alcohol
Make 3-bromo-8-methyl-quinoline-6-alcohol (preparation method is described in the stage 1 of embodiment 13) and sodium iodide, cupric iodide and N with step 1 similar methods with embodiment 13A, N, N ', N '-tetramethyl--ethane-1, the 2-diamine reactant, produce the product that needs, 3-iodo-8-methyl-quinoline-6-alcohol is brown solid (MH +286).
1H NMR(CDCl 3)δppm：2.61(3H，s)；6.92(1H，d)；7.20(1H，d)；8.60(1H，dd)；8.79(1H，d)。
Step 2:(3-iodo-8-methyl-quinoline-6-base oxygen)-preparation of methylthio group-ethyl acetate
With with step 1 similar methods in stage 2 of embodiment 5, make 3-iodo-8-methyl-quinoline-6-alcohol and chloro-methyl sulfenyl-acetic acid ethyl reaction, produce (3-iodo-8-toluquinoline-6-base oxygen)-methylthio group-ethyl acetate, be yellow solid (MH +418).
With with step 2 similar methods in stage 2 of embodiment 5, will (3-iodo-8-methyl-quinoline-6-base oxygen)-methylthio group-hydrolysis of ethyl acetate, produce (3-iodo-8-methyl-quinoline-6-base oxygen)-methylthio group-acetate, be yellow solid ([M-1] +388).
With with stages 2 similar methods of embodiment 1, will (3-iodo-8-methyl-quinoline-6-base oxygen)-methylthio group-acetate and tert-butylamine condensation, produce the N-tertiary butyl-2-(the basic oxygen of 3-iodo-8-methyl-quinoline-6-)-2-methylthio group-ethanamide, be white solid ([M+1] +445).
1H NMR(CDCl 3)δppm：1.41(9H，s)；2.20(3H，s)；2.54(3H，s)，5.56(1H，s)；6.42(1H，s)；6.98(1H，d)；7.32(1H，dd)；8.42(1H，d)，8.95(1H，d)。
The compound 52 of table 72A uses similar methods to prepare with 2-cyano group-1-methoxyl group-third-2-base amine.
Embodiment 13D
This embodiment has illustrated the preparation of 2-(3-bromo-8-chloro-quinoline-6-base the oxygen)-N-tertiary butyl-2-methylthio group-ethanamide (compound 12 of table 62)
With with step 2 similar methods of embodiment 6, with 6-amino-3-bromo-8-chloroquinoline [preparation method is at J Am Chem Soc (1955), 77, provide among the 4175-4176] hydrolysis, produce 3-bromo-8-chloro-6-hydroxyquinoline, be brown solid.
1H NMR (CDCl 3) δ ppm:7.00 (1H, d); 7.52 (1H, d); 8.17 (1H, d); 8.77 (1H, d); The OH signal that non-constant width is arranged at 7ppm.
With with step 1 similar methods in stage 2 of embodiment 5, make 3-bromo-8-chloro-6-hydroxyquinoline and 2-bromo-2-methylthio group acetic acid ethyl reaction, produce 2-(3-bromo-8-chloroquinoline base-6-oxygen)-2-methylmercaptan ethyl acetoacetic ester, be yellow jelly.
1H NMR(CDCl 3)δppm：1.37(3H，t)；2.23(3H，s)；4.28-4.40(2H，m)；5.69(1H，s)；7.08(1H，d)；7.68(1H，d)；8.25(1H，d)；8.90(1H，d)。
With with step 2 similar methods in stage 2 of embodiment 5, be 2-(3-bromo-8-chloroquinoline base-6-oxygen)-2-methylthio group acetate with 2-(3-bromo-8-chloroquinoline base-6-oxygen)-2-methylmercaptan ethyl hydrolysis of ethyl acetate, be colorless solid.
1H NMR(d6-DMSO)δppm：2.17(3H，s)；6.16(1H，s)；7.52(1H，d)；7.86(1H，d)；8.68(1H，d)；8.93(1H，d)。
With with stages 2 similar methods of embodiment 1, with 2-(3-bromo-8-chloroquinoline base-6-oxygen)-2-methylthio group acetate and tert-butylamine condensation, produce 2-(3-bromo-8-chloro-quinoline-6-base the oxygen)-N-tertiary butyl-2-methylthio group-ethanamide (compound 12 of table 62), be white solid, m.p.160-161 ℃.
1H NMR(CDCl 3)δppm：1.43(9H，s)；2.20(3H，s)；5.57(1H，s)；6.39(1H，bs)；7.11(1H，d)；7.62(1H，d)；8.29(1H，d)；8.92(1H，d)。
Embodiment 13E
This embodiment has illustrated the preparation of 2-(3-bromo-8-iodo-quinoline-6-base the oxygen)-N-tertiary butyl-2-methylthio group-ethanamide (compound 12 of table 62A)
The preparation of stage 13-bromo-8-iodo-quinoline-6-alcohol
Step 1
With 2,2,3-tribromo propionic aldehyde (5.9g) is handled acetate (40ml) solution of 2-iodo-4-N-methyl-p-nitroaniline (5.3g), and mixture 110 ℃ of heating 2 hours, is cooled to it room temperature and filtration afterwards.The solid that leaches washs with ether, suspends in water and handles with saturated sodium bicarbonate.Use ethyl acetate extraction, the Sodium Persulfate drying is filtered and reduction vaporization, produces required product, and 3-bromo-8-iodo-6-nitro-quinoline is yellow solid (silicon-dioxide after the chromatographic separation; Hexane/ethyl acetate) (M +379).
1H NMR(CDCl 3)δppm：8.50(1H，d)；8.72(1H，d)；9.08(1H，d)；8.62(1H，d)。
Step 2
With with step 1 similar methods in stage 1 of embodiment 6,3-bromo-8-iodo-6-nitro-quinoline is handled with concentrated hydrochloric acid and iron powder, produce 3-bromo-8-iodo-quinoline-6-base amine, be cream-coloured powder ((M+1) +351).
1H NMR(CDCl 3)δppm： 1H NMR(CDCl 3)δppm：4.04(1H，bs)；6.77(1H，bs)；7.79(1H，bs)；7.98(1H，bs)；8.67(1H，bs)。
Step 3
With method described in the step 2 of embodiment 6, the 3-bromo-8-iodo-quinoline-6-base amine hydrolysis with step 2 gained produces 3-bromo-8-iodo-quinoline-6-alcohol, is white solid ((M+2) +352).
1H NMR(DMSO-d6)δppm：7.20(1H，d)；7.98(1H，d)；8.52(1H，d)；8.73(1H，d)；40.50(1H，s)。
Stage 2
Step 1
With with step 1 similar methods in stage 2 of embodiment 5, make 3-bromo-8-iodo-quinoline-6-alcohol (from step 3) and chloro-methyl sulfenyl-methyl acetate reaction in stage 1 of embodiment 13E, produce (3-bromo-8-iodo-quinoline-6-base oxygen)-methyl-sulfenyl-methyl acetate, be yellow solid ((M+2) +470).
1H NMR(CDCl 3)δppm：2.22(3H，s)；3.89(3H，s)；5.70(1H，s)；7.15(1H，d)；8.15(1H，d)；8.20(1H，d)；8.86(1H，d)。
With with step 2 similar methods in stage 2 of embodiment 5, (3-bromo-8-iodo-quinoline-6-base oxygen)-methyl-sulfenyl-methyl acetate hydrolysis is become (3-bromo-8-iodo-quinoline-6-base oxygen)-methyl-sulfenyl-acetate, be yellow solid ((M+2) +456).
1H NMR(d6-DMSO)δppm：2.17(3H，s)；6.13(1H，s)；7.59(1H，d)；8.20(1H，d)；8.59(1H，d)；8.89(1H，d)。
With with stages 2 similar methods of embodiment 1, with (3-bromo-8-iodo-quinoline-6-base oxygen)-methyl-sulfenyl-acetate and tert-butylamine condensation, produce 2-(3-bromo-8-iodo-quinoline-6-base the oxygen)-N-tertiary butyl-2-methylthio group-ethanamide (compound 12 of table 62A), be white solid, m.p.171-172 ℃.
1H NMR(CDCl 3)δppm：1.43(9H，s)；2.19(3H，s)；5.57(1H，s)；6.39(1H，bs)；7.19(1H，d)；8.10(1H，d)；8.20(1H，d)；8.89(1H，d)。
Embodiment 14
This embodiment has illustrated the fungicide performance of formula (1) compound.
Compound is tested with following method in the test of leaf dish.Test compounds is dissolved in DMSO and is diluted to 200ppm in water.To the mould test of ultimate corruption the time, compound dissolution is diluted to 20ppm in DMSO and in water.
Erysiphe graminis f.sp.hordei (big wheat powdery mildew): the Folium Hordei Vulgaris section is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Erysiphe graminis f.sp.tritici (wheat powdery mildew): the wheat leaf section is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Puccinia recondita f.sp.tritici (wheat leaf rust): the wheat leaf section is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
The withered septoria musiva of grain husk (wheat grain husk pinta): the wheat leaf section is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Circle nuclear cavity bacteria (net blotch of barley): the Folium Hordei Vulgaris section is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Pyricularia oryzae (rice blast): rice leaf dish is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Gray botrytis (grey mold): Kidney bean leaf dish is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Phytophthora infestan (late blight of potato on the tomato): the tomato leaf dish is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Grape is given birth to single shaft mould (oidium of grape vine): the grape leaf dish is placed on the agar of 24-hole flat board, with the spray solution of test compounds.After treating complete drying, need 12-24 hour, with the spore suspension inoculation leaf dish of fungi.After passing through hatching of suiting, the activity of four days postevaluation compounds of inoculation is as preventative fungi activity.
Wheat septoria (leaf spot): the conidium of the fungi of cryopreservation is directly sneaked in the nutrition gravy (PDB potato glucose meat soup).After (DMSO) solution of test compounds put into microtitration flat board (96-hole gauge lattice), add the nutrition gravy that contains fungal spore.Test slab is hatched at 24 ℃, determine the inhibition situation of growth after 72 hours.
Machete sickle spore (root rot): the conidium of the fungi of cryopreservation is directly sneaked in the nutrition gravy (PDB potato glucose meat soup).After (DMSO) solution of test compounds put into microtitration flat board (96-hole gauge lattice), add the nutrition gravy that contains fungal spore.Test slab is hatched at 24 ℃, determine the inhibition situation of growth after 48 hours.
Ultimate corruption mould (samping off): will sneak in the potato glucose meat soup by the mycelial fragment that fresh liquid is cultivated the fungi that makes.The dimethyl sulphoxide solution of test compounds is diluted with water to 20ppm, puts into 96 hole microtitration flat boards then, add the nutrition gravy that contains fungal spore.Test slab is hatched at 24 ℃, determine the inhibition situation of growth after 48 hours.
Following compounds (compound number was a table number in the bracket of back before this) provides at least 60% control to following fungi infestation when 200ppm:
It is mould that grape is given birth to single shaft, compound 8 (57), 12 (1), 12 (13), 12 (15), 12 (36), 12 (44), 12 (47), 12 (55), 12 (57), 12 (58), 12 (58A), 12 (59), 12 (60), 12 (62), 12 (62B), 12 (72), 12 (72A), 12 (81), 13 (57), 16 (57), 42 (57), 43 (57), 47 (57), 47 (72), 48 (57), 52 (13), 52 (57), 52 (58), 52 (58A), 52 (59), 52 (60), 52 (61), 52 (72), 52 (81), 53 (1), 53 (62B), 60 (57), 62 (31), 63 (57), 68 (57), 68 (61), 68 (62), 68 (72), 82 (57), 133 (81), 144 (57), 152 (57), 153 (57), 155 (57), 164 (57), 171 (57), 180 (57), 183 (57), 187 (57), 189 (81), 210 (57), 220 (57), 220 (61), 220 (62), 224 (57), 224 (61), 227 (1), 226 (57), 227 (57), 230 (57), 231 (50), 235 (57);
Phytophthora infestan, compound 12 (1), 12 (13), 12 (15), 12 (44), 12 (57), 12 (58), 12 (58A), 12 (59), 12 (60), 12 (62), 12 (62B), 12 (70), 12 (72), 12 (72A), 13 (57), 16 (57), 39 (57), 40 (57), 42 (57), 43 (57), 47 (57), 47 (62), 47 (72), 48 (57), 49 (57), 50 (57), 50 (62), 50 (72), 52 (13), 52 (57), 52 (58), 52 (58A), 52 (59), 52 (60), 52 (72), 52 (72A), 52 (81), 53 (62B), 60 (57), 62 (57), 63 (57), 68 (57), 68 (61), 68 (72), 70 (58), 82 (57), 82 (65), 84 (58), 89 (57), 102 (57), 198 (57), 220 (57), 220 (61), 220 (62), 220 (72), 224 (57), 224 (62), 231 (57); 236 (57);
Wheat powdery mildew, compound 4 (57), 7 (57), 8 (57), 11 (57), 12 (1), 12 (13), 12 (44), 12 (50), 12 (57), 12 (58), 12 (58A), 12 (61), 12 (62), 12 (62B), 12 (72A), 13 (57), 16 (61), 16 (62), 27 (57), 35 (50), 35 (57), 35 (58), 39 (57), 42 (57), 43 (57), 45 (57), 46 (57), 47 (57), 47 (62), 47 (72), 48 (57), 49 (57), 50 (57), 50 (61), 50 (62), 50 (70), 50 (72), 52 (13), 52 (50), 52 (57), 52 (58), 52 (58A), 52 (61), 52 (70), 52 (72), 52 (72A), 53 (57), 53 (62B), 62 (57), 63 (57), 68 (61), 68 (62), 68 (72), 70 (57), 70 (58), 71 (57), 76 (57), 84 (57), 84 (58), 89 (57), 124 (57), 124 (58), 144 (57), 150 (61), 152 (57), 157 (57), 158 (57), 159 (57), 160 (57), 164 (57), 165 (57), 172 (57), 173 (57), 176 (57), 178 (57), 180 (57), 198 (57), 200 (57), 202 (57), 209 (57), 220 (62), 220 (82), 224 (61), 224 (83), 231 (57), 236 (57), 237 (57)
Pyricularia oryzae, compound 12 (50), 12 (57), 12 (58), 35 (57), 35 (58), 38 (58), 46 (57), 47 (57), 52 (57), 84 (57), 120 (57), 166 (57), 189 (57), 200 (57);
Gray botrytis, compound 8 (57), 16 (61), 38 (61), 12 (67), 47 (62), 12 (83a), 48 (57), 50 (57), 50 (62), 52 (50), 52 (57), 52 (67), 68 (62), 68 (61), 68 (72), 120 (58), 122 (50), 124 (58), 133 (57), 164 (57), 169 (57), 207 (57), 211 (61), 220 (61);
Big wheat powdery mildew, compound 4 (57), 6 (57), 8 (57), 12 (1), 12 (13), 12 (15), 12 (50), 12 (57), 12 (58), 12 (61), 13 (57), 27 (57), 33 (57), 35 (50), 35 (57), 35 (58), 38 (50), 38 (58), 38 (61), 39 (57), 40 (57), 42 (57), 43 (57), 45 (57), 47 (57), 48 (57), 49 (57), 50 (57), 52 (13), 52 (50), 52 (57), 52 (58), 52 (61), 52 (67), 53 (57), 59 (57), 60 (57), 62 (57), 63 (57), 65 (57), 70 (13), 70 (50), 70 (57), 70 (58), 71 (57), 84 (50), 84 (57), 84 (58), 85 (57), 89 (57), 102 (57), 120 (58), 122 (57), 122 (58), 124 (58), 124 (61), 128 (58), 133 (81), 144 (57), 150 (58), 150 (61), 152 (57), 153 (57), 157 (57), 158 (57), 161 (57), 163 (57), 164 (57), 177 (57), 178 (57), 180 (57), 183 (57), 185 (57), 189 (57), 189 (58), 192 (57), 198 (57), 200 (57), 211 (61), 212 (57), 216 (57);
Puccinia triticinia, compound 12 (58A), 12 (72A), 35 (50), 47 (57), 47 (72), 52 (58A), 220 (72);
The withered septoria musiva of grain husk, compound 12 (50), 12 (61), 47 (57), 52 (50), 84 (50), 84 (57), 120 (57), 133 (57), 198 (57);
Wheat septoria, compound 12 (1), 12 (36), 12 (44), 12 (47), 12 (55), 12 (57), 12 (62), 12 (83A), 12 (83B), 16 (57), 16 (61), 16 (72), 47 (62), 12 (58A), 12 (60), 47 (62), 12 (62A), 12 (62B), 12 (72a), 47 (72), 50 (61), 50 (62), 50 (72), 52 (52), 52 (58A), 52 (61), 52 (62B), 52 (72), 52 (72A), 68 (57), 68 (61), 68 (72), 220 (57), 220 (61), 220 (62), 220 (72), 224 (57), 224 (61), 224 (62), 230 (50), 226 (57), 228 (57), 230 (57), 235 (57), 236 (57), 237 (57).
Machete sickle spore, compound 12 (58A), 12 (62), 12 (62A), 12 (62B), 12 (72A), 16 (57), 16 (61), 16 (62), 47 (62), 47 (72), 50 (62), 50 (72), 52 (58A), 52 (72A), 68 (62), 68 (57), 68 (61), 68 (72), 220 (57), 220 (61), 220 (62), 220 (72), 235 (57).
Following compounds (compound number was a table number in the bracket of back before this) provides at least 60% control to following fungi infestation when 20ppm:
Ultimate corruption is mould, compound 2 (57), 12 (1), 12 (13), 12 (15), 12 (47), 12 (55), 12 (57), 12 (58), 12 (58A), 12 (59), 12 (60), 12 (62), 12 (62B), 12 (65), 12 (70), 12 (81), 12 (83b), 12 (36), 12 (44), 13 (57), 16 (72), 27 (57), 35 (57), 35 (58), 35 (81), 39 (57), 40 (57), 42 (57), 43 (57), 47 (57), 47 (62), 47 (72), 48 (57), 49 (57), 50 (57), 50 (62), 50 (72), 52 (57), 52 (58), 52 (58A), 52 (59), 52 (62B), 52 (72), 52 (72A), 52 (81), 59 (57), 60 (57), 62 (57), 63 (57), 65 (57), 68 (57), 68 (61), 68 (72), 70 (57), 70 (58), 70 (81), 82 (57), 84 (57), 84 (58), 89 (57), 120 (57), 122 (57), 122 (58), 124 (57), 133 (57), 133 (58), 133 (81), 185 (57), 189 (44), 189 (57), 189 (81), 220 (57), 220 (62), 224 (57), 231 (57), 235 (57), 236 (57).

Claims (19)

1. the compound of general formula (1):
Figure FSB00000250826400011
Wherein
Ar is a phenyl, and it is optional by one, two or three substituting groups replacements, and described substituting group is independently selected from halogen, cyano group and C 1-6Alkyl; The optional pyridyl that is replaced by halogen, the optional benzothiazolyl that is replaced by halogen; Dibenzofuran group, its optional by one, two or three are independently selected from halogen and C 1-6The substituting group of alkyl replaces; Quinolyl, it is optional by one, two or three substituting groups replacements, and described substituting group is independently selected from halogen, C 1-4Alkyl, halo C 1-4Alkyl, phenyl, naphthyl, anthryl, phenanthryl, contain one or more O, N or the heteroatomic 5-of S or 6-unit aromatic ring, it can condense with one or more phenyl ring;
R 1It is methyl;
R 2Be H or methyl;
R 3It is the tertiary butyl, 1,1,1-three fluoro-2-methyl-prop-2-bases, 2-cyano group third-2-base, 1-methoxyl group-2-methyl-prop-2-base, 1-methylthio group-2-methyl-prop-2-base, 1-methoxyl group-3-methyl fourth-3-base, 2-cyano group-1-methoxyl group-third-2-base, 2-methoxycarbonyl-third-2-base, 2-methylamino carbonyl third-2-base, 2-methylol-1-methoxyl group-third-2-base or 1-methoxyl group-2-methoxymethyl-third-2-base;
L is O or S; With
N is 0,1 or 2.
2. the described compound of claim 1 (1), wherein Ar is 3,5-dichlorophenyl, 3,4,5-trimethylphenyl, 4-bromo-3,5-3,5-dimethylphenyl or 4-cyano group-3,5-3,5-dimethylphenyl.
3. the described compound of claim 1 (1), wherein Ar is 5-chloropyridine-3-base.
4. the described compound of claim 1 (1), wherein Ar is benzothiazole-6-base.
5. the described compound of claim 1 (1), wherein Ar is diphenylene-oxide-2-base.
6. the described compound of claim 1 (1), wherein Ar is 3-bromoquinoline-6-base, 3-chloroquinoline-6-base, 3-fluorine quinoline-6-base, 3,8-two bromoquinolines-6-base, 3-bromo-8-chloroquinoline-6-base, 3-bromo-8-toluquinoline-6-base, 3-phenylquinoline-6-base or 3-pyridin-4-yl quinoline-6-base.
7. the described compound of claim 1 (1), wherein Ar is 3-bromoquinoline-6-base, 3,8-two bromo-quinoline-6-base, 3-bromo-8-chloroquinoline-6-base or 3-bromo-8-toluquinoline-6-base.
8. the described compound of claim 1 (1), wherein Ar is 3,8-difluoro-quinoline-6-base, 3-fluoro-8-chloroquinoline-6-base, 3-fluoro-8-bromoquinoline-6-base, 3-fluoro-8-iodine quinoline-6-base, 3-fluoro-8-toluquinoline-6-base, 3,8-dichloroquinoline-6-base, 3-chloro-8-fluorine quinoline-6-base, 3-chloro-8-bromoquinoline-6-base, 3-chloro-8-iodine quinoline-6-base, 3-chloro-8-toluquinoline-6-base, 3,8-bromoquinoline-6-base, 3-bromo-8-chloroquinoline-6-base, 3-bromo-8-fluorine quinoline-6-base, 3-bromo-8-iodine quinoline-6-base, 3-bromo-8-toluquinoline-6-base, 3,8-iodine quinoline-6-base, 3-iodo-8-chloroquinoline-6-base, 3-iodo-8-bromoquinoline-6-base, 3-iodo-8-fluorine quinoline-6-base or 3-iodo-8-toluquinoline-6-base.
9. the described compound of claim 1 (1), wherein Ar is 8-halogenated quinoline-6-base or 8-toluquinoline-6-base.
10. compound according to claim 1 (1), wherein R 3Be 2-methylol-1-methoxyl group-third-2-base or 1-methoxyl group-2-methoxymethyl-third-2-base.
11. compound according to claim 1 (1), wherein L is O.
12. compound according to claim 1 (1), wherein n is 0.
13. a method for preparing the described compound of claim 1, wherein n is 0, and this method comprises that (a) makes formula (4) compound
Figure FSB00000250826400031
With halide reagent reaction, (b) gained formula (5) compound
Figure FSB00000250826400032
In the presence of alkali, react production (6) compound with compd A r-OH
Figure FSB00000250826400033
(c) in the presence of alkali, this compound is changed into the acid of corresponding formula (7)
Figure FSB00000250826400034
(d) should acid and the amine reaction of formula (8)
Figure FSB00000250826400035
Wherein Ar, R 1, R 2, R 3As claim 1 definition, R 5Be C 1-4Alkyl,
And use sulfuration reagent to prepare the wherein formula of L=S (1) compound by corresponding amide.
14. a method for preparing the described compound of claim 1, wherein n is 1 or 2, and this method comprises that (a) makes formula (4) compound
With halide reagent reaction, (b) gained formula (5) compound
Figure FSB00000250826400042
In the presence of alkali, react with compd A r-OH, production (6) compound,
Figure FSB00000250826400043
(c) with this compound of oxidizer treatment, acquisition formula (9) or (10) compound,
Figure FSB00000250826400044
(d) in the presence of alkali, this compound is transformed the corresponding acid of an accepted way of doing sth (11) or (12),
Figure FSB00000250826400045
(d) amine of the compound of formula (11) or (12) and formula (8) reaction
Wherein Ar, R 1, R 2, R 3As claim 1 definition, R 5Be C 1-4Alkyl,
And use sulfuration reagent to prepare the wherein formula of L=S (1) compound by corresponding amide.
15. a method for preparing the described compound of claim 1, wherein n is 0, and this method comprises that (a) makes formula (2) compound
Figure FSB00000250826400047
With halide reagent reaction, the formula that (b) so obtains (3) compound
Figure FSB00000250826400051
Use formula R 1The alkane thiol of-SH transforms an accepted way of doing sth (6) compound,
Figure FSB00000250826400052
R wherein 1Define as claim 1, (c) in the presence of alkali, this compound is transformed the corresponding acid of an accepted way of doing sth (7)
Figure FSB00000250826400053
(d) amine of this acid and formula (8) reaction
Wherein Ar, R 1, R 2, R 3As claim 1 definition, R 5Be C 1-4Alkyl,
And use sulfuration reagent to prepare the wherein formula of L=S (1) compound by corresponding amide.
16. a method for preparing the described compound of claim 1, wherein n is 0, and this method comprises that (a) makes formula (13) compound
Figure FSB00000250826400055
With the amine reaction of formula (8),
Figure FSB00000250826400056
Form the compound of formula (14),
Figure FSB00000250826400061
(b) handle this compound with halide reagent, production (16) compound
(c) this compound reacts with Ar-OH in the presence of alkali,
Wherein Ar, R 1, R 2, R 3As claim 1 definition,
And use sulfuration reagent to prepare the wherein formula of L=S (1) compound by corresponding amide.
17. a method for preparing the described compound of claim 1, wherein n is 0, and this method comprises that (a) makes formula (15) compound
Figure FSB00000250826400063
Amine with formula (8) in the presence of alkali reacts,
Figure FSB00000250826400064
Form formula (16) compound,
Figure FSB00000250826400065
(b) this compound reacts with Ar-OH in the presence of alkali,
Wherein Ar, R 1, R 2, R 3As claim 1 definition,
And use sulfuration reagent to prepare the wherein formula of L=S (1) compound by corresponding amide.
18. a fungicide composition contains formula as claimed in claim 1 (1) compound of fungicidal significant quantity and carrier or the thinner that suits.
19. the method for antagonism or control plant pathogenic fungi, this method comprises seed, plant or seed location or soil or any other plant growth medium that the described compound of the claim 1 of fungicidal significant quantity (1) or the described composition of claim 18 is applied to plant, plant.
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